Clinical Follow-Up of 11 Argentinian CD40L-Deficient Patients with 7 Unique Mutations Including the So-Called “Milder” Mutants

CD40 ligand (CD40L) deficiency is an X-linked combined immunodeficiency characterized by impaired class switch recombination. We analyzed clinical and molecular findings in 11 Argentinian patients from seven unrelated families. The mean age at onset of symptoms was 1.1 years (0.5-3.0 years) and the 10 alive patients have a median age of 17 years. We identified two nonsense mutations, including R11X reported as a "hypomorphic" defect, four missense mutations, and one point deletion. Although R11X was associated herein with parvovirus B19-anemia and higher Igs levels as previously described, histoplasmosis and Pneumocystis jiroveci pneumonia were also present. Other so-called "milder" mutation, T254M, was present in three related patients clinically and immunologically undistinguishable from the rest of the cohort. Furthermore, 10 of the 11 patients, having heterogeneous mutations, never had persistent neutropenia, none presented Cryptosporidium sp. infection nor developed liver-biliary tract disease, highlighting the debatable concept of "milder" mutations.     

Bifocal Right Ventricular Resynchronization for the Failing Right Ventricle

The present case illustrates that in patients with right ventricular (RV) failure and right bundle branch block it is possible to resynchronize the RV without further worsening RV or left ventricular (LV) pump function, even in cases with various degrees of atrioventricular block. The acute response to different pacing configurations was analyzed in terms of dP/dt variations. Bifocal RV pacing (His bundle plus RV outflow tract pacing) achieved the best acute results and was chosen for permanent pacing. This pacing configuration was associated to clinical and echocardiographic improvement. (PACE 2011; 34:e78–e81)     

Anti-inflammatory Activity of Polyphosphazene-based Naproxen Slow-release Systems

A biocompatible and biodegradable polyphosphazene bearing phenylalanine ethyl ester, imidazole and chlorine (10.7:1:2.5 molar ratio) as substituents of the phosphorus atoms of the polymer backbone was studied for the preparation of polymeric naproxen slow-release systems. Discs 2.5 cm in diameter and 0.5 mm (thin) or 0.65 mm (thick), loaded, respectively, with 20 and 13.5% naproxen, showed different drug release kinetics, the thin matrices releasing naproxen at a faster rate and for a shorter time. In-vivo studies in rats demonstrated the pharmacological efficacy of these two different delivery systems in the inhibition of acute or chronic inflammatory diseases. Subcutaneous implantation of the thin matrices in rats was found to reduce carrageenan oedema induced both 1 h and 7 days after implantation. Rats implanted with thick matrices showed a reduction in chronic inflammation caused by adjuvant arthritis. Approximately 78% inhibition of arthritic oedema was found 28 days after subcutaneous administration of the matrices whereas 28.7% inhibition was found after daily oral administration of naproxen. Blood levels of naproxen in arthritic rats after matrix implantation showed the presence of drug up to day 28. These positive results have encouraged us to study a controlled-release system suitable for use in man.     

Consumption of buprenorphine and other drugs among heroin addicts under ambulatory treatment: results from cross–sectional studies in 1988 and 1990

We assessed the prevalence of consumption of buprenorphine and other drugs among heroin addicts under ambulatory treatment in two cross-sectional studies conducted in 1988 (188 subjects) and in 1990 (197 subjects). Patients were enrolled in one of three different programmes: methadone maintenance programme (MMP), antagonist maintenance programme (AMP) and drug-free programme (DFP). Information given by participants was compared with results of urine screening for drugs. Urine samples were tested using enzyme immunoassay for the detection of heroin, cocaine, dextropropoxyphetie, cannabis and benzodiazopnies, and radioimmunoassay for buprenorphine. Sixty-six percent of patients in 1988 and 71% of patients in 1990 reported having consumed buprenorphine at some time during their history of drug dependence (period prevalence) and 5.9% and 6.1%, respectively, tested positive to the drug (point prevalence). In over 70% of these patients consumption was by the intravenous route. Consumption of cannabis, cocaine and benzodiazepines was also very high in the study population. Overall, patients in the DFP group consumed the largest number of the drugs tested, while those in the AMP group consumed the smallest number. Abuse of buprenorphine could be more widespread than previously reported.     

A Random DNA Sequencing,Computer-Based Approach for the Generation of a Gene Map of Molluscum Contagiosum Virus

The genome of Molluscum contagiosum virus (MCV) has a high G+C content, which largely differs from those of vaccinia virus (VAC) and other characterized poxviruses. This has precluded the use of DNA hybridization for the identification of MCV genes and the further establishment of the virus genetic map. To circumvent this problem, we have partially sequenced clones containing virus restriction endonuclease fragments, which were derived by either single or double-digestion of genomic DNA from the subtype I of MCV. The DNA sequences were translated and used to search protein data bases. This analysis resulted in the finding of high-scoring matches to data base entries, including forty-five VAC genes. In addition, MCV-specific sequences that encoded protein domains of known function (i.e. DNA J domain) were found. The locations of MCV clones were inferred from the presumed colinearity of both MCV and VAC genomes, and further confirmed by PCR technology. The data presented here led to the construction of a partial genetic map of MCVI, which revealed that the order and orientation of a large number of MCV genes were equivalent to those of their VAC homologues. The conserved gene arrangement was apparently disrupted in the terminal regions, where MCV sequences showing homologies with the VAC counterparts were not found.     

ABSENCE OF ANTISPERM SURFACE ANTIBODIES IN PREPUBERTAL BOYS WITH CRYPTORCHIDISM AND OTHER ANOMALIES OF THE INGUINOSCROTAL REGION BEFORE AND AFTER SURGERY

PURPOSE: Although the prepubertal immune system cannot recognize postmeiotic germ cell antigens, an overall 21 to 28% incidence of antisperm antibodies directed at these antigens has been reported preoperatively in prepubertal children with cryptorchidism and other inguinoscrotal anomalies. We investigated the prevalence of antisperm antibodies in these prepubertal patients before and after surgery. MATERIALS AND METHODS: We examined 82 prepubertal boys 0.6 to 13.2 years old, including 33 with unilateral cryptorchidism, 21 with inguinoscrotal anomalies and 28 who were normal. IgG, IgM and IgA antisperm antibodies were determined by the indirect Immunobead test. Serum testing was repeated 1 and 2 years postoperatively and annually for 2 more years in the normal children. Also sera from 183 infertile men 21 to 47 years old with a history of cryptorchidism and/or inguinal hernia operated on in childhood were similarly studied. RESULTS: Of the adults 70 (39%) tested IgG positive, including 12 (7%) who were also IgA positive, and all tested IgM negative. Repeat measurements were negative for all IgG, IgA and IgM isotypes in all children, patients and controls. CONCLUSIONS: We conclude that there are no antibodies to sperm surface antigens in prepubertal children with cryptorchidism and inguinoscrotal anomalies before and within 2 years after surgery. Autoimmunity against postmeiotic sperm membrane antigens is apparent in adults only.     

Atrioventricular Nodal Tachycardia in a Patient with Anomalous Inferior Vena Cava with Azygos Continuation and Persistent Left Superior Vena Cava

A 39-year-old female patient was referred for ablation of recurrent episodes of atrioventricular nodal reentrant tachycardia. A combination of an anomalous inferior vena cava with azygos continuation and a persistent left superior vena cava was discovered. A nonfluoroscopic navigation system was very useful for catheter ablation of the tachycardia in this unusual case of anomalous venous system of the heart.     

Potent agonists of growth hormone-releasing hormone

Analogs of the 29 amino acid sequence of growth hormone-releasing hormone (GH-RH) with agmatine (Agm) in position 29 have been synthesized by the solid phase method, purified, and tested in vitro and in vivo. The majority of the analogs contained desaminotyrosine (Dat) in position 1, but a few of them had Tyr¹, or N-MeTyr¹. Some peptides contained one or more additional l - or d -amino acid substitutions in positions 2, 12, 15, 21, 27, and/or 28. Compared to the natural sequence of GH-RH(1-29)NH₂, [Dat′,Ala¹⁵]GH-RH(1-28)Agm (MZ-3-191) and [d -Ala²,Ala¹⁵]GH-RH(l-28)Agm (MZ-3-201) were 8.2 and 7.1 times more potent in vitro, respectively. These two peptides contained Met²⁷. Their Nle²⁷ analogs, [Dat^I,Ala¹⁵,Nle²⁷]GH-RH(1-28)Agm(MZ-2-51), prepared previously (9), and [^D-Ala²,Ala¹⁵,Nle²⁸]GH-RH(l-28)Agm(MZ-3-195) showed relative in vitro potencies of 10.5 and 2.4, respectively. These data indicate that replacement of Met²⁷ by Nle²⁷ enhanced the GH-releasing activity of the analog when the molecule contained Dat¹-Ala² residues at the N-terminus, but peptides containing Tyr¹-D-Ala² in addition to Nle²⁷ showed decreased potencies. Replacement of Ser²⁸ with Asp in multi-substituted analogs of GH-RH(l-28)Agm resulted in a decrease in in vitro potencies compared to the parent compound. Thus, the Ser²⁸-containing MZ-2-51, and [Dat¹,Ala¹⁵,d -Lys²¹,Nle²⁷]GH-RH(l-28)Agm, its Asp²⁸ homolog (MZ-3-149), possessed relative activities of 10.5 and 5.6, respectively. In vivo after the iv injection, the analogs [Dat¹,Ala¹⁵,Nle²⁷,Asp²⁸]GH-RH(l-28)Agm (MZ-3-149), [Dat¹, Ala¹⁵]GH-RH(l-28)Agm, (MZ-3-191) and [d -Ala²,Ala^,5]GH-RH(l-28)Agm (MZ-3-201) showed a potency equivalent to 7.6, 4.9 and 3.3 times that of GH-RH(1-29)NH₂, respectively, at 5 min and 20.3, 4.3 and 1.7 times higher, respectively, at 15 min. After sc administration, analogs MZ-3-149, MZ-3-191, and MZ-3-201 were shown to be 63.7, 55.2 and 56.8 times more potent than the parent hormone at 15 min and 57.6, 60.6, and 42.6 times more active, respectively, at 30 min. In addition, MZ-3-149 had prolonged GH-releasing activity as compared to the standard, and proved to be more potent than MZ-2-51, the most active member of our previous series (8, 9). Our studies indicate that very potent GH-RH analogs can result from the combination of agmatine in position 29 with other substitutions.