Efficacy and safety of peg-IFN alfa-2a with ribavirin for the treatment of HCV/HIV coinfected patients who failed previous IFN based therapy.

BACKGROUND: Interferon (IFN) regimens for HCV treatment are less effective in HCV/HIV-coinfected patients. There are no effective treatments for patients who fail IFN therapies. We examined the safety and efficacy of peginterferon alfa-2a (peg-IFNalpha-2a) plus ribavirin (RBV) in 41HCV/HIV-coinfected patients non-responsive to prior IFN treatment. METHODS: Patients received peg-IFNalpha-2a (180mg/week) plus RBV (800mg/day) for 24 weeks (n=41). At week 24, patients with non-detectable HCV RNA or > or =2-log decrease from baseline, received peg-IFNalpha-2a (180mg/week) plus RBV (800mg/day) for 24 weeks further. Patients not responding to treatment at week 24 were discontinued. RESULTS: Intent to treat (ITT) sustained viral response (SVR) was 21.9%. Patients who received at least 24 weeks of peg-IFNalpha-2a plus RBV treatment (n=35), SVR rates were 25.7%. SVR was associated with significant improvements in liver histology grade (p=0.02), stage (p=0.02), and fibrosis progression rate (FPR) (p=0.03). Patients that failed to achieve SVR had statistically significant decreases in grade (p=0.09) and FPR (p=0.01). CONCLUSION: peg-IFNalpha-2a plus RBV is effective and safe to achieve SVR in HCV/HIV coinfected patients non-responsive to prior IFN treatment. Patients that achieve SVR have significant improvements in liver histology parameters. In patients that do not achieve SVR there are histological benefits beyond virological response that suggest that peg-IFNalpha-2a+RBV therapy may decrease risk of progression to end stage liver disease.     

Complex malformations of the female genital tract. New types and revision of classification

BACKGROUND: Complex malformations of the female genital tract are often incorrectly identified, treated and reported, probably due to not considering the malformation as a cause of the clinical symptoms and neither the embryological origin of the different elements of the genitourinary tract. METHODS: Complex malformations are studied and classified, and new types are presented. The new types of complex malformations presented are: (i) Cases of unilateral vaginal or cervico-vaginal atresia with renal agenesis and uterine duplication, with or without communication between hemiuteri; (ii) the unilateral Rokitansky syndrome; and (iii) the combination in the same patient of unilateral Rokitansky syndrome (Müllerian defect) on one side and blind vagina and ipsilateral renal agenesis syndrome (Wolffian defect) on the other side. RESULTS: A revised version of the clinical and embryological classification of genital malformations is presented and an associated diagram points out the origin of these malformations. CONCLUSIONS: These genital malformative anomalies reaffirm our hypothesis about the embryology of the human vagina as deriving from the Wolffian ducts and the Müllerian tubercle; and they show that gynecologists should be aware of the related symptoms and the embryology of the female genital tract in order to achieve a better comprehension of the malformations for their right correction or therapeutic approach.     

Successful treatment of retinal angiomatous proliferation by photodynamic therapy.

PURPOSE: The purpose of this study is to describe a patient with retinal angiomatous proliferation (RAP) treated successfully by photodynamic therapy. METHODS: A 74-year-old white woman was referred to our clinic for evaluation as a result of progressive decrease of vision in the right eye. Visual acuity was 20/100 in the affected right eye. The findings of fluorescein and indocyanine green angiography were consistent with a diagnosis of RAP, and cystoid macular edema was also revealed by optical coherence tomography (OCT). Photodynamic therapy (PDT) was carried out because of visual deterioration and localization of the RAP. RESULTS: The RAP was treated with PDT, and an improvement in visual acuity to 20/60 was noted 4 months after treatment and 20/40 after 6 months. The resolution of the lesion was confirmed by fluorescein angiography, indocyanine green angiography, and OCT. CONCLUSIONS: Photodynamic therapy can be effective for the treatment of RAP when it is associated with visual acuity decrease and is located near the fovea.     

Elucidating the clinical significance of two <Emphasis Type="Italic">PMS2</Emphasis> missense variants coexisting in a family fulfilling hereditary cancer criteria

The clinical spectrum of germline mismatch repair (MMR) gene variants continues increasing, encompassing Lynch syndrome, Constitutional MMR Deficiency (CMMRD), and the recently reported MSH3-associated polyposis. Genetic diagnosis of these hereditary cancer syndromes is often hampered by the presence of variants of unknown significance (VUS) and overlapping phenotypes. Two PMS2 VUS, c.2149G>A (p.V717M) and c.2444C>T (p.S815L), were identified in trans in one individual diagnosed with early-onset colorectal cancer (CRC) who belonged to a family fulfilling clinical criteria for hereditary cancer. Clinico-pathological data, multifactorial likelihood calculations and functional analyses were used to refine their clinical significance. Likelihood analysis based on cosegregation and tumor data classified the c.2444C>T variant as pathogenic, which was supported by impaired MMR activity associated with diminished protein expression in functional assays. Conversely, the c.2149G>A variant displayed MMR proficiency and protein stability. These results, in addition to the conserved PMS2 expression in normal tissues and the absence of germline microsatellite instability (gMSI) in the biallelic carrier ruled out a CMMRD diagnosis. The use of comprehensive strategies, including functional and clinico-pathological information, is mandatory to improve the clinical interpretation of naturally occurring MMR variants. This is critical for appropriate clinical management of cancer syndromes associated to MMR gene mutations.     

Annular lipoatrophic panniculitis of the ankles

We report a girl with lipophagic lobular panniculitis of unknown origin located on her ankles leading to circumferential fat atrophy of the ankles, a condition usually referred to as "annular lipoatrophy of the ankles." According to our patient's features and five additional cases reported so far, we conclude that this condition is actually an end-stage manifestation of an idiopathic lobular panniculitis of children localized to the lower part of the lower limbs. An association with some autoimmune manifestations is highlighted.     

Metrological traceability of values for α-amylase catalytic concentration assigned to a commutable calibrator materials

BackgroundThe International Standard ISO 18153 describes how to assure the metrological traceability of catalytic concentration values assigned to commercial calibration materials following the reference measurement system. We applied this approach to the standardization of α-amylase measurements.MethodsTraceable values of catalytic activity with measurement uncertainty were assigned to three commercial calibrator materials using α-amylase primary reference measurement procedure described by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). The metrological traceable to the SI units calibration was validated by measuring human serum and plasma samples using the primary reference procedure and two routine commercial measurement procedures using different substrates (4,6-ethylidene(G1)-4-nitrophenyl(G7)-α-(1→4)-d-maltoheptaoside (EPS) and 2-chloro-4-nitrophenyl-α-d-maltotrioside (CNP)) and calibrated with the traceable materials. Previously the commutability of the commercial calibration materials was verified.ResultsProcedures comparison showed that the primary reference procedure and routine procedures have the same analytical specificity. The commercial calibrators tested showed to be commutable and were used to recalibrate the routine measurement procedures. The agreement of procedures improves after recalibration with commutable calibrator materials.ConclusionsThe implementation of a reference system for α-amylase measurements was demonstrated that assures the traceability of patients' results to SI units and to harmonize the results obtained by two different routine procedures.     

Carbohydrate-based experimental therapeutics for cancer, HIV/AIDS and other diseases

This review, primarily for general readers, briefly presents experimental approaches to therapeutics of cancer, HIV/AIDS and various other diseases based on advances in glycobiology and glycochemistry. Experimental cancer and HIV/AIDS vaccines are being developed in attempts to overcome weak immunological responses to carbohydrate-rich surface antigens using carriers, adjuvants and novel carbohydrate antigen constructs. Current carbohydrate-based vaccines are used for typhus, pneumonia, meningitis; vaccines for anthrax, malaria and leishmaniasis are under development. The link between O-linked beta-N-acetylglucosamine glycosylation and protein phosphorylation in diseases including diabetes and Alzheimer's disease is also explored. Carbohydrate-associated drugs that are in current use or under development, such as heparan sulfate binders, lectins, acarbose, aminoglycosides, tamiflu and heparin, and technologies using carbohydrate and lectin microarrays that offer improved diagnostic and drug development possibilities, are described. Advances in carbohydrate synthesis, analysis and manipulation through the emerging fields of glycochemistry and glycobiology are providing new approaches to disease therapeutics.     

Tuberculosis diagnosis and multidrug resistance testing by direct sputum culture in selective broth without decontamination or centrifugation

Tuberculosis culture usually requires sputum decontamination and centrifugation to prevent cultures from being overgrown by contaminating bacteria and fungi. However, decontamination destroys many tuberculous bacilli, and centrifugation often is not possible in resource-poor settings. We therefore assessed the performance of Mycobacterium tuberculosis culture with unprocessed samples plated directly by using tuberculosis-selective media and compared this procedure to conventional culture using centrifuge decontamination. Quadruplicate aliquots of strain H37RV were cultured in 7H9 broth with and without selective antimicrobials and after centrifuge decontamination. The subsequent comparison was made with 715 sputum samples. Split paired sputum samples were cultured conventionally with centrifuge decontamination and by direct culture in tuberculosis-selective media containing antibiotics. Centrifuge decontamination reduced tuberculosis H37RV colonies by 78% (P < 0.001), whereas direct culture in tuberculosis-selective media had no inhibitory effect. Similarly, in sputum cultures that were not overgrown by contaminants, conventional culture yielded fewer tuberculosis colonies than direct culture (P < 0.001). However, the sensitivity of conventional culture was greater than that of direct culture, because samples were less affected by contamination. Thus, of the 340 sputum samples that were tuberculosis culture positive, conventional culture detected 97%, whereas direct culture detected 81% (P < 0.001). Conventional and direct cultures both took a median of 8.0 days to diagnose tuberculosis (P = 0.8). In those direct cultures that detected drug resistance or susceptibility, there was a 97% agreement with the results of conventional culture (Kappa agreement statistic, 0.84; P < 0.001). Direct culture is a simple, low-technology, and rapid technique for diagnosing tuberculosis and determining drug susceptibility. Compared to that of conventional culture, direct culture has reduced sensitivity because of bacterial overgrowth, but in basic laboratories this deficit may be outweighed by the ease of use.     

Intranasal immunization with a proteoliposome-derived cochleate containing recombinant gD protein confers protective immunity against genital herpes in mice

The purpose of this study was to investigate the potential of intranasal (IN) immunization with Neisseria meningitides B proteoliposome (AFPL1) and AFPL1-derived cochleate (AFCo1), containing glycoprotein D (gD) of herpes simplex virus type 2 (HSV-2) for induction of protective immunity against genital herpes infection in mice. We could show that IN immunization with both AFPL1 and AFCo1 containing gD induced gD-specific IgG antibody and lymphoproliferative responses. However, IFN-γ response could only be detected in CD4⁺ splenic cells and genital lymph node cells of the AFCo1gD immunized mice upon recall antigen stimulation in vitro. Importantly, IN immunization with AFCo1gD could elicit a complete protection against an otherwise lethal vaginal challenge with HSV-2, while the AFPL1gD immunized mice were only partially protected. Further, we could show that the IFN-γ response and protective immunity observed after IN immunization with AFCo1gD are mediated via the adaptor molecule myeloid differentiation factor 88. These data may have implications for the development of a mucosal vaccine against genital herpes.