Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes.

BACKGROUND: Rituximab, a chimeric monoclonal antibody against CD20, is increasingly used in the treatment of B-cell lymphomas and autoimmune conditions. Transient peripheral B-cell depletion is expected following rituximab therapy. Although initial clinical trials did not show significant hypogammaglobulinaemia, reports of this are now appearing in the literature. METHODS: We performed a retrospective review of patients previously treated with rituximab that were referred to Clinical Immunology with symptomatic or severe hypogammaglobulinaemia. Patient clinical histories, immunological markers, length of rituximab treatment and need for intravenous immunoglobulin replacement therapy (IVIG) were evaluated. An audit of patients receiving rituximab for any condition in a 12-month period and frequency of hypogammaglobulinaemia was also carried out. RESULTS: We identified 19 post-rituximab patients with persistent, symptomatic panhypogammaglobulinaemia. Mean IgG level was 3.42 ± 0.4 g/l (normal range 5.8-16.3 g/l). All patients had reduced or absent B-cells. Haemophilus Influenzae B, tetanus and Pneumococcal serotype-specific antibody levels were all reduced and patients failed to mount an immune response post-vaccination. Nearly all of them ultimately required IVIG. The mean interval from the last rituximab dose and need for IVIG was 36 months (range 7 months-7 years). Of note, 23.7% of 114 patients included in the audit had hypogammaglobulinaemia. CONCLUSION: With the increasing use of rituximab, it is important for clinicians treating these patients to be aware of hypogammaglobulinaemia and serious infections occurring even years after completion of treatment and should be actively looked for during follow-up. Referral to clinical immunology services and, if indicated, initiation of IVIG should be considered.

Penile granulomatosis presenting as pseudoangioedema.

Many conditions may present as angioedema. We report a case of a 46 year-old man presenting with intermittent episodes of penile swelling. Following a series of investigations, he was diagnosed with genital granulomatosis. Ano-genital granulomatosis is a rare chronic inflammatory condition and that can present as diffuse penile, scrotal, vulvar or ano-perineal swelling with non-caseating non-necrotising granulomas on histology.

In pursuit of excellence: an integrated care pathway for C1 inhibitor deficiency.

There are estimated to be approximately 1500 people in the United Kingdom with C1 inhibitor (C1INH) deficiency. At BartsHealth National Health Service (NHS) Trust we manage 133 patients with this condition and we believe that this represents one of the largest cohorts in the United Kingdom. C1INH deficiency may be hereditary or acquired. It is characterized by unpredictable episodic swellings, which may affect any part of the body, but are potentially fatal if they involve the larynx and cause significant morbidity if they involve the viscera. The last few years have seen a revolution in the treatment options that are available for C1 inhibitor deficiency. However, this occurs at a time when there are increased spending restraints in the NHS and the commissioning structure is being overhauled. Integrated care pathways (ICP) are a tool for disseminating best practice, for facilitating clinical audit, enabling multi-disciplinary working and for reducing health-care costs. Here we present an ICP for managing C1 inhibitor deficiency.

Autosomal recessive chronic granulomatous disease presenting with cutaneous dermatoses and ocular infection.

Dermatoses such as eczematous dermatitis and cutaneous infection are recognized presentations of primary immunodeficiency (PID). However, atopic dermatitis affects approximately 10% of infants, and cutaneous infections are not uncommon in children, therefore the challenge for the dermatologist is to distinguish the few patients that have PID from the many that do not. We report on a 6-year-old girl who was ultimately diagnosed with autosomal recessive chronic granulomatous disease (AR-CGD) after presenting to various hospitals with dermatitis, scalp plaques recalcitrant to treatment, and recurrent infections over a 3-year period, and describe some aspects of her diagnosis and management. This report highlights the importance of considering rare disorders such as AR-CGD in the differential diagnosis of recurrent or recalcitrant dermatological infections in children.

IgE-mediated allergy to local anaesthetics: separating fact from perception: a UK perspective.

Local anaesthetic (LA) agents have been routinely used in dentistry, ophthalmology, minor surgery, and obstetrics since the late nineteenth century. Reports relating to adverse reactions and LA allergy have appeared in the published literature for several years. However, the incidence of true, IgE-mediated LA allergy remains uncertain and is presumed to be very low. We critically reviewed the English language literature on suspected LA allergy and its investigation with the aim of estimating the reported prevalence and analysing the role of different tests currently used to identify and confirm LA allergy. Twenty-three case series involving 2978 patients were identified and analysed. Twenty-nine of these patients had true IgE-mediated allergy to LA, thus confirming the reported prevalence of LA allergy in large series to be <1% (0.97%). The protocols used in the investigation of these patients have also been discussed. Evidence from this review confirms the rarity of IgE-mediated allergy to LA and supports an investigation strategy based on using the clinical history to select patients for skin testing and challenge. We believe that such a triage process would alleviate pressures on allergy services without compromising patient safety.

Management of granulomatous common variable immunodeficiency diagnosed in pregnancy: a case report.

Common variable immunodeficiency (CVID) is a rare condition that affects women of childbearing age with important implications in pregnancy. It is characterised by low immunoglobulins (Igs), poor antibody response and a susceptibility to recurrent infections. The cornerstone of management of CVID is Ig replacement. As the transfer of IgG across the placenta in the third trimester of pregnancy is necessary for protection of the infant in the first months of life, failure to recognise this condition and treat it appropriately can have adverse consequences for the neonate, as well as the mother. Here we describe the complex perinatal medical management of a 34-year-old woman who was diagnosed with CVID in the 26th week of pregnancy.

In vivo analysis of DNase I hypersensitive sites in the human CFTR gene.

BACKGROUND: The cystic fibrosis transmembrane conductance regulator gene (CFTR) shows a complex pattern of expression. The regulatory elements conferring tissue-specific and temporal regulation are thought to lie mainly outside the promoter region. Previously, we identified DNase I hypersensitive sites (DHS) that may contain regulatory elements associated with the CFTR gene at -79.5 and at -20.5 kb with respect to the ATG and at 10 kb into the first intron. MATERIALS AND METHODS: In order to evaluate these regulatory elements in vivo we examined these DHS in a human CFTR gene that was introduced on a yeast artificial chromosome (YAC) into transgenic mice. The 310 kb human CFTR YAC was shown to restore the pheno-type of CF-null mice and so is likely to contain most of the regulatory elements required for tissue-specific expression of CFTR. RESULTS: We found that the YAC does not include the -79.5 kb region. The DHS at -20.5 kb is present in the chromatin of most tissues of the transgenic mice, supporting its non-tissue-specific nature. The DHS in the first intron is present in a more restricted set of tissues in the mice, although its presence does not show complete concordance with CFTR expression. The intron I DHS may be important for the higher levels of expression found in human pancreatic ducts and in lung submucosal glands. CONCLUSION: These data support the in vivo importance of these regulatory elements.

Complementation of null CF mice with a human CFTR YAC transgene.

We have made transgenic mice carrying a 320 kb YAC with the intact human cystic fibrosis transmembrane regulator (CFTR) gene. Mice that only express the human transgene were obtained by breeding with Cambridge null CF mice. One line has approximately two copies of the intact YAC. Mice carrying this transgene and expressing no mouse cftr appear normal and breed well, in marked contrast to the null mice, where 50% die by approximately 5 days after birth. The chloride secretory responses in these mice are as large or larger than in wild-type tissues. Expression of the transgene is highly cell type specific and matches that of the endogenous mouse gene in the crypt epithelia throughout the gut and in salivary gland tissue. However, there is no transgene expression in some tissues, such as the Brunner's glands, where it would be expected. Where there are differences between the mouse and human pattern of expression, the transgene follows the mouse pattern. We have thus defined a cloned fragment of DNA which directs physiological levels of expression in many of the specific cells where CFTR is normally expressed.

Copy number-dependent expression of a YAC-cloned human CFTR gene in a human epithelial cell line.

Initial studies for gene therapy of cystic fibrosis have used heterologous promoters to drive expression of the cystic fibrosis transmembrane regulator (CFTR) cDNA. An alternative approach would be to have constructs based on the endogenous promoter which could give tissue-specific and normal, regulated levels of expression. The DNA elements necessary for this remain unidentified so we have investigated CFTR expression from a 310 kb yeast artificial chromosome (YAC) clone which contains the intact human CFTR gene consisting of 27 exons spread over 230 kb of genomic DNA and also about 50 kb of 5' DNA. In order to distinguish the gene on the YAC, a restriction site change was introduced into the 3' untranslated region of the gene in the YAC. The YAC was then transferred into the human colonic adenocarcinoma cell line Caco-2 which expresses endogenous CFTR. The CFTR gene on the YAC was found to be well expressed in the Caco-2 cells and, in the two cell lines analysed, the ratio of YAC-derived mRNA to endogenous mRNA was the same as the ratio of YAC DNA to endogenous DNA. This indicates that each copy of the CFTR gene on a YAC integrated in the Caco-2 cells is being expressed at approximately the same level as each of the endogenous genes. Thus, the YAC clone contains all the long-range elements necessary to confer full levels of expression, independent of position of integration, in human Caco-2 cells. Deletion of this YAC clone should allow the elucidation of the DNA elements controlling human CFTR expression and the development of constructs for gene therapy.

Relationship of the third heart sound to transmitral flow velocity deceleration.

BACKGROUND: The third heart sound (S3) occurs shortly after the early (E-wave) peak of the transmitral diastolic Doppler velocity profile (DVP). It is thought to be due to cardiohemic vibrations powered by rapid deceleration of transmitral blood flow. Although the presence, timing, and clinical correlates of the S3 have been extensively characterized, derivation and validation of a causal, mathematical relation between transmitral flow velocity and the S3 are lacking. METHODS AND RESULTS: To characterize the kinematics and physiological mechanisms of S3 production, we modeled the cardiohemic system as a forced, damped, nonlinear harmonic oscillator. The forcing term used a closed-form mathematical expression for the deceleration portion of the DVP. We tested the hypothesis that our model's predictions for amplitude, timing, and frequency of S3 accurately predict the transthoracic phonocardiogram, using the simultaneously recorded transmitral Doppler E wave as input, in three subject groups: those with audible pathological S3, those with audible physiological S3, and those with inaudible S3. CONCLUSIONS: We found excellent agreement between model prediction and the observed data for all three subject groups. We conclude that, in the presence of a normal mitral valve, the kinematics of filling requires that all hearts have oscillations of the cardiohemic system during E-wave deceleration. However, the oscillations may not have high enough amplitude or frequency to be heard as an S3 unless there is sufficiently rapid fluid deceleration (of the Doppler E-wave contour) with sufficient cardiohemic coupling.

Comparison of diastolic filling models and their fit to transmitral Doppler contours.

Anatomic/physiologic and kinematic mathematical models of diastolic filling which employ (lumped) parameters of diastolic function have been used to predict or characterize transmitral flow. The ability to determine model parameters from clinical transmitral flow, the Doppler velocity profile (DVP), is equivalent to solving the "inverse problem" of diastole. Systematic model-to-model and model-to-data comparison has never been carried out, in part due to the requirement that DVPs be digitized by hand. We developed, tested and verified a computerized method of DVP acquisition and reproduction, and carried out numerical determination of model-to-model and model-to-data goodness-of-fit. The transmitral flow velocity of two anatomic/physiologic models and one kinematic model were compared. Each model's ability to fit computer-acquired and reproduced transmitral DVPs was assessed. Results indicate that transmitral flow velocities generated by the three models are 'graphically indistinguishable and are able to fit the E-wave of clinical DVPs with comparable mean-square errors. Nonunique invertibility of the anatomic/physiologic models was verified, i.e., multiple sets of model parameters could be found that fit a single DVP with comparable mean-square error. The kinematic formulation permitted automated, unique, model-parameter determination, solving the "inverse problem" for the Doppler E-wave. We conclude that automated, quantitative characterization of clinical Doppler E-wave contours using this method is feasible. The relation of kinematic parameters to physiologic variables is a subject of current investigation.

Rhabdomyoma of prostate.

An asymptomatic nineteen-year-old white man presented with a markedly enlarged and indurated prostate. Urologic evaluation including cystoscopy, prostatic ultrasound, pelvic computerized tomography (CT) scan, and pelvic nuclear magnetic resonance imaging revealed a prostatic mass impinging on the bladder. Transrectal biopsies returned the pathologic diagnosis of rhabdomyomatous hamartoma. We report the first case in the English literature of extracardiac rhabdomyoma found in the male genitourinary tract.

Anatomic explanation for bulbar urethral pseudostricture.

Interpretation of retrograde urethrography can be complicated by the appearance of an apparent well-defined proximal bulbous urethral stricture which later is not identified on urethroscopy. Two illustrative cases of this confusing finding are presented, and the anatomic explanation is reviewed.

Simple aid for upright voiding after partial penectomy.

Inadequate penile length after partial penectomy may result in the socially unacceptable inability to project the urinary stream over the scrotum. A simple adaptation of a 60 cc syringe is described as an aid to contain and direct the urinary stream.

Traumatic testicular torsion: case report.

Trauma has been reported as an infrequent cause of testicular torsion. A case of trauma-induced testicular torsion is reported and literature reviewed. The inclusion of torsion in the differential diagnosis of post-traumatic acute scrotal pain is important to ensure early appropriate management.

Choice of antibiotic for lower urinary tract infections in men.

When lower urinary tract infection is present in a male patient, prostatic involvement must be considered. A 30-day course of treatment with one of the antibiotics shown to be superior in treating prostatitis is recommended. It is hoped that this program will eliminate needless progression or relapse of infection and reduce the subsequent risk for development of chronic prostatitis.

Small cell carcinoma of prostate.

Small cell anaplastic carcinoma (SCC) involving the prostate is extremely unusual, either as a primary or as a secondary metastatic focus. A case of SCC presenting as prostatic obstruction and diagnosed with prostate biopsy is presented and the literature reviewed.