Diagnosis and management of oncogenic cervical human papillomavirus infection

Cervical HPV infection should be managed less as a typical STI and more as a strong risk factor predisposing to cervical cancer development. HPV infection is undeniably transmitted predominately through sexual contact.However, the fact that more than 80% of women followed over time will acquire at least one HR-HPV infection reflects the ubiquitous nature of the infection and the ease of transmission. Although the behavioral profiles typically associated with an increased risk for STI (including lifetime partner number, age at first intercourse, and so forth) will certainly lead to an increased risk for HPV detection, there is a high absolute prevalence of HPV even among women who have few lifetime sex partners. It could be argued that to counsel patients for an HPV infection as an STI would be counterproductive, as short of absolute abstinence, the prevention of infection is difficult and treatment options, short of excisional procedures for neoplasia, are limited.The real promise held in this area is the availability of an apparently highly effective prophylactic HPV vaccine, targeting at least HPV 16, 18, 6, and 11[33,34]. This vaccine cocktail, if it achieved 100% coverage, could theoretically prevent 50% to 70% of invasive cervical cancers and most genital warts. Vaccination will be required among women before initiation of sexual contact, presumably among girls 10 to 13 years of age. Many programmatic issues remain regarding the implementation of HPV vaccine programs, including the marketing of the vaccine as STI or cancer prevention,as reviewed in detail by Gravitt and Shah [72]. Even in the era of potentially effective vaccines, screening for cervical cancer is likely to remain a priority in cervical cancer prevention programs for at least several decades. Vaccine trials have proven high short-term efficacy; however, these effects were clearly type-specific and antibody titers gradually decrease postvaccination. It is unclear whether the protection will remain over an individual's lifetime without vaccine booster, and oncogenic HPV infections not targeted by vaccination will continue to contribute to risk for development of cervical intraepithelial neoplasia and cancer. Therefore, although the public health success of HPV vaccination is undoubtedly promising, the role of cervical cancer screening as a secondary prevention effort should not be trivialized. In fact, the nature of screening programs should continue to be reevaluated in the context of effective but limited spectrum vaccines.     

A prospective study of human papillomavirus (HPV) type 16 DNA detection by polymerase chain reaction and its association with acquisition and persistence of other HPV types

Human papillomavirus (HPV)-16 causes about half the cases of cervical cancer worldwide and is the focus of HPV vaccine development efforts. Systematic data are lacking as to whether the prevention of HPV-16 could affect the equilibrium of infection with other HPV types and thus alter the predicted impact of vaccination on the occurrence of cervical neoplasia. Therefore, the associations of HPV-16 detection with subsequent acquisition of other HPV types and with the persistence of concomitantly detected HPV types were examined prospectively among 1124 initially cytologically normal women. Preexisting HPV-16 was generally associated with an increased risk for subsequent acquisition of other types. HPV-16 did not affect the persistence of concomitant infections, regardless of type. These findings suggest that the prevention or removal of HPV-16 is not likely to promote the risk of infection with other types, a theoretical concern with current vaccination efforts.     

A novel homozygous mutation at the GAA gene in Mexicans with early-onset Pompe disease

Glycogen-storage disease type II, also named Pompe disease, is caused by the deficiency of the enzyme acid alpha-glucosidase, which originates lysosomal glycogen accumulation leading to progressive neuromuscular damage. Early-onset Pompe disease shows a debilitating and frequently fulminating course. To date, more than 300 mutations have been described; the majority of them are unique to each affected individual. Most early-onset phenotypes are associated with frameshift mutations leading to a truncated alpha-glucosidase protein with loss of function. Founder effects are responsible from many cases from few highprevalence world regions. Herein we described two apparently unrelated cases affected with classical early-onset Pompe disease, both pertaining to a small region from Central Mexico (the State of San Luis Potosí), the same novel homozygous frameshift mutation at gene GAA (c.1987delC) was demonstrated in both cases. This GAA gene deletion implies a change of glutamine to serine at codon 663, and a new reading frame that ends after 33 base pairs, which leads to the translation of a truncated protein. This report contributes to widen the knowledge on the effect of pathogenic mutations in Pompe disease. Here we postulate the existence of a founder effect.Key words: Early-onset Pompe disease, Acid maltase deficiency, Founder effectGlycogen storage disease type II (Online Mendelian Inheritance in Man, OMIM, accession number 232300), also called Pompe disease, was described by Johannes C. Pompe in 1932. The disorder is caused by a deficiency of the enzyme acid alpha-glucosidase (acid maltase, EC 3.2.1.20, Swiss) which originates lysosomal glycogen accumulation leading to lysosomal swelling, cellular damage and dysfunction (1-3). Affected individuals develop progressive neuromuscular damage, showing a debilitating and frequently fulminating course on the classical, early-onset type of the disease. Other main findings are hypertrophic cardiomyopathy, hypotonia, hepatomegaly, macroglossia, feeding problems and breath difficulty. Currently it is recognized that the late form of Pompe disease has a very variable phenotype that can be confused with a wide range of neuromuscular, pulmonary and cardiovascular diseases with mild, moderate or severe symptoms that present either alone or combined (4-6).Pompe disease has an autosomal recessive inheritance and it is caused by more than 300 mutations that occur all over the gene coding for acid alpha-glucosidase (GAA) located at locus 17q25.2q25.3. The molecular phenomenon responsible of the different types of clinical expression occur by the presence of two either homozygous or compound heterozygous pathogenic mutations in early-onset Pompe cases, whereas late-onset Pompe have one variant and one pathogenic mutation (7). The majority of disease-causing mutations are unique; nonetheless, relatively frequent mutations have been described in certain populations with a possible founder effect traced from the original mutated carrier to the newly occurring cases. Affected cases have been described worldwide with a few high-prevalence regions like South-Africa, Taiwan and Holland (1, 8-10).Herein, we described two unrelated cases affected with classical early-onset Pompe disease, both pertaining to the same small Mexican region, with the same novel homozygous frameshift mutation at gene GAA (c.1987delC), identified by complete gene sequencing.     

The arterial wall: a new pharmacological and therapeutic target*

Summary— In recent years, two key concepts having numerous interrelationships were advanced for the understanding of various cardiovascular diseases: the “endothelial dysfunction” and the “arterial remodelling”. Both endothelial dysfunction and arterial remodelling occur in various pathologies including essential hypertension, heart failure, atherosclerosis, restenosis after angioplasty, and pulmonary hypertension, and have modified the therapeutic approach by offering new pharmacological targets: specific receptors not only at the site of the vascular smooth muscle cells but also on the endothelial cells, growth factors that stimulate proliferation of smooth muscle, and receptors and enzymes of the extra-cellular matrix. Among the various substances under research, the present review will discuss angiotensin II receptor antagonists, endothelin receptor antagonists, nitrates-NO donors, potassium channel activators, and substances interfering with proteoglycans and other components of the extra-cellular matrix.     

Topical naphazoline in treatment of myopathic ptosis

We instilled naphazoline Hcl (0.1%), an imidazole derivative with preferential alpha-2 activity, in 17 eyes of 12 patients with myopathic ptosis due to involvement of the levator palpebrae superioris, in the attempt to selectively stimulate Müller's smooth muscle. Naphazoline significantly widened the palpebral fissure with little change in pupillary diameter and no significant change in ocular pressure, visual acuity and near point determination. However, a reduction of the effect, probably due to tachyphylaxis, was noticed when using naphazoline regularly several times a day for few weeks. In conclusion naphazoline has powerful cosmetical and functional effects in mild to moderate myopathic ptosis above all if taken occasionally.     

Human breast cancer in vivo: H-1 and P-31 MR spectroscopy at 1.5 T

To assess the potential of in vivo magnetic resonance (MR) spectroscopy for breast cancer, hydrogen-1 and phosphorus-31 MR spectra of five malignant human breast tumors were compared with those of unaffected breast tissue. The water-to-fat ratio was high in the tumors (average, 2.2) but low in the unaffected tissue (average, 0.3). The P-31 spectrum of normal breast tissue showed low levels of phosphomonoesters (PMEs), inorganic phosphate, phosphodiesters (PDEs), and ATP. In addition, an intense phosphocreatine (PCr) signal was observed in breast tissue of young women: The relative intensities of the PCr and ATP signals had a mean value of 1.9. The tumor spectrum showed elevated levels of PMEs, Pi, and PDEs, while no PCr was seen (PCr/ATP less than 0.2). In two breast cancers treated with radiation therapy, resulting in a decrease of tumor volume of more than 50%, a similar change in the tumor P-31 spectrum was observed: An intense PCr signal developed (PCr/ATP = 1.1). Control experiments indicated that the appearance of PCr after radiation therapy was the result of a radiation-induced metabolic change in the tumor itself.     

Evaluation of non-invasive techniques to assess vasoconstriction in healthy volunteers using methoxamine as a probe drug

Non-invasive methods for assessment of the vascular effects of antimigraine drugs were evaluated with respect to their utility, variability and sensitivity in a double-blind, placebo-controlled, three-period crossover study in six healthy volunteers using an intravenous vasoconstrictor, methoxamine, as a probe drug. Changes in the internal diameter of the brachial and radial arteries were measured using ultrasound which had low between-day and within-day coefficients of variation. Peak systolic velocity (PSV), time-averaged velocity (TAV), total flow, resistance (RI) and pulsatility indices (PI) were measured by Doppler from one arterial wave form. Whilst PSV and TAV increased with methoxamine, because of bradycardia, changes in PI and RI were difficult to interpret. An automatic oscillametric cuff, a mercury-in-silastic strain gauge method and the "Finapres", finger arterial blood pressure monitor were used to follow changes in systolic blood pressure (SBP). The strain gauge technique underestimated arm SBP compared to the oscillometric method but clearly showed drug-related increases whilst the Finapres did not reflect changes in blood pressure detected by the other methods.