IgG4-related disease confined to the laryngopharynx: a case report highlighting the complexities in diagnosis for this rare cause of stridor.

This case represents only the 15th reported incidence of IgG4-related disease (IgG4-RD) affecting the laryngopharynx, adding diagnostic and therapeutic data for this rare condition and helping to inform the future management of these patients. A 66-year-old man presented with airway symptoms, and investigations by otolaryngology, cardiology and respiratory teams did not provide a clear diagnosis. Repeat biopsies of the laryngopharynx eventually confirmed a clinicopathological diagnosis of IgG4-RD. Treatment with prednisolone and methotrexate was successful. When infective and malignant causes of adult stridor have been excluded, inflammatory causes should be considered. The diagnosis of IgG4-RD isolated to the laryngopharynx may be delayed when using the widely accepted American College of Rheumatology classification criteria because it excludes upper aerodigestive tract features. IgG4-RD isolated to the laryngopharynx is extremely rare. This means a multidisciplinary approach is vital in ensuring timely diagnosis and treatment. Better diagnostic criteria are also needed.

The palliative management of non-islet cell tumour hypoglycaemia with glucocorticoids and somatostatin analogues in an unresectable hepatocellular carcinoma.

Non-islet cell tumour hypoglycaemia (NICTH) results from paraneoplastic insulin-like growth factor-II (IGF-II) secretion and its potent insulin-like effect. It causes recurrent, often severe, hypoglycaemic episodes, which is detrimental to quality of life. There is limited evidence regarding best supportive care in unresectable tumours. A 76-year-old woman presented with hypoglycaemic collapse. A new diagnosis of unresectable hepatocellular carcinoma (HCC) was made. The IGF-II:IGF-I ratio was 11.0, which confirmed NICTH. The octreoscan showed avid disease. The main problem was symptomatic nocturnal hypoglycaemia. Curative treatment options were not possible in this case and treatment focused on preventing symptomatic hypoglycaemia. Inpatient treatment was with high carbohydrate nasogastric (NG) feeds, prednisolone and somatostatin analogue (octreotide) infusion. Once stabilised, the patient was discharged with NG feeds, prednisolone and a long-acting somatostatin analogue (sandostatin). The patient received successful end-of-life care with her family as per her wishes, without requiring readmission. The treatments were well-tolerated and effective in preventing symptomatic hypoglycaemic episodes. The combination of high carbohydrate NG feed with prednisolone and somatostatin analogues was effective in preventing symptomatic hypoglycaemia. Somatostatin analogues had a useful steroid sparing role. Larger case series are warranted to clarify the management of NICTH patients with placebo-controlled studies to determine the role of somatostatin analogues.

Trends and publication rates of abstracts presented at the British Association of Head and Neck Oncologists' (BAHNO) annual meetings: 2009 - 2015.

The British Association of Head and Neck Oncologists (BAHNO) hosts an annual meeting at which research from all specialties involved in the management of head and neck oncology is presented. We have analysed the rate of publication of the abstracts presented, and reviewed the finalised programmes from the meetings between 2009 and 2015. The 2014 meeting was excluded as it was a combined international meeting. Key terms were searched in PubMed and Google Scholar to identify publications in peer-reviewed journals. If none was identified, these platforms were searched for the authors' names. Published abstracts were excluded. Study and journal demographic data were extracted. A total of 363 abstracts were presented, including 75 oral, 271 poster, and 17 of unclear presentation method. The total publication rate was 31.1%, representing 46.7% of oral abstracts and 27.3% of poster presentations. The mean time to publication was 16.5 months. Research was published in 45 individual journals with a mean (range) impact factor of 2.559 (0.886-36.418). There was a trend towards an increasing number of presentations over time with a decreasing publication rate. However, there was no trend in mean impact factor by year. The publication rate of abstracts presented at the BAHNO annual meetings is comparable with that of other large otolaryngology and head and neck conferences. The mean impact factor has not previously been utilised within this field, but may prove a useful metric that enables monitoring of the quality of presented research and comparison of the impact of the conferences.

"I think they're all basically the same": parents' perceptions of human papilloma virus (HPV) vaccine compared with other adolescent vaccines.

BACKGROUND: Human papillomavirus (HPV) vaccination is recommended for routine administration at ages 11-12 years. However, uptake is lower than for other vaccines that are also routinely recommended for adolescents (MCV4 and Tdap). Understanding parental perceptions of HPV vaccine compared with other vaccines may help to inform strategies to increase uptake. METHODS: Parents and caregivers (n = 45) of adolescents ages 10-18 years from a low-income, ethnic minority population participated in a qualitative study. Interviews were transcribed verbatim and coded for emergent themes. RESULTS: Many participants perceived the HPV vaccine to be similar to other routine vaccines. Noted similarities included the vaccines' ability to prevent disease, similar methods of administration and belief in health care providers' recommendation. Some parents noted the greater benefit of HPV vaccine in preventing cancer, which was viewed as a serious disease. Parents also noted the different mode of transmission (sexual) for HPV, which evoked mixed opinions. CONCLUSION: Overall, most participants viewed the HPV vaccine in a positive light and similar to other adolescent vaccines with the added benefit of cancer prevention. Strategies that treat all three vaccines equally such as presenting them similarly as a 'bundle' to parents or considering policy initiatives such as school entry requirements might help increase raise coverage for HPV vaccine.

The use of alloderm as an adjunct in the closure of the bladder - Cloacal exstrophy complex.

OBJECTIVE: To decrease the incidence of vesicocutaneous fistulae (VCF), intra-pubic stitch erosion (IPE) and intrasymphyseal plate erosion (ISE) of bladder or cloacal exstrophy in patients undergoing reclosure, we sought additional bulking material to place between the posterior urethral/bladder neck and pubic closures. MATERIAL AND METHODS: In 43 patients (2005-2009) undergoing exstrophy/cloacal exstrophy closure or reclosure, we placed human acellular dermis (HAD) between the posterior urethral/bladder neck and pubic closures. The thickest piece of HAD available was placed above the urethra and bladder neck, and attached to the pelvic floor with sutures of 4-0 Vicryl prior to pubic bone apposition. RESULTS: Twenty-three were primary and 20 were reclosures. Of the 23 primary closures, 17 were classic exstrophy and six were cloacal exstrophy. Of the 20 reclosures, 17 were classic exstrophy and three were cloacal exstrophy. Thirty-four had an osteotomy and nine did not, at the time of closure. No patient experienced failure of closure, a VCF, an IPE or an ISE into the urethra after pubic apposition, or other complication related to the use of HAD. One patient had a superficial wound infection, and one had premature suprapubic tube dislodgement requiring replacement in the operating room. CONCLUSION: From the success of this novel technique in failed closures, we have begun using HAD as an adjunct in all exstrophy closures.

Treatment of whole blood (WB) and red blood cells (RBC) with S-303 inactivates pathogens and retains in vitro quality of stored RBC.

A pathogen inactivation (PI) process has been developed using the frangible anchor linker effector (FRALE) compound S-303. A series of experiments were performed in whole blood (WB) to measure the level of viral and bacterial inactivation. The results showed that 0.2mM S-303 and 2mM glutathione (GSH) inactivated >6.5 logs of HIV, >5.7 logs of Bluetongue virus, >7.0 logs of Yersinia enterocolitica, 4.2 logs of Serratia marcescens, and 7.5 logs of Staphylococcus epidermidis. Recent development for S-303 is focused on optimization of the PI process for red blood cell concentrates (RBC). A series of studies in RBC showed that 0.2mM S-303 and 20mM GSH inactivated approximately 5 logs or greater of Y. enterocolitica, E. coli, S. marcescens, S. aureus, HIV, bovine viral diarrhoea virus, bluetongue virus and human adenovirus 5. In both applications of the S-303 process, in vitro parameters of RBC function and physiology were retained compared to conventional RBC. Results from these studies indicate that S-303 can be applicable for PI of RBC and WB.

A UK consensus on the management of the bladder in multiple sclerosis.

Bladder symptoms in multiple sclerosis (MS) are common and distressing but also highly amenable to treatment. A meeting of stakeholders involved in patients' continence care, including neurologists, urologists, primary care, MS nurses and nursing groups was recently convened to formulate a UK consensus for management. National Institute for Health and Clinical Excellence (NICE) criteria were used for producing recommendations based on a review of the literature and expert opinion. It was agreed that in the majority of cases, successful management could be based on a simple algorithm which includes using reagent sticks to test for urine infection and measurement of the post micturition residual urine volume. This is in contrast with published guidelines from other countries which recommend cystometry. Throughout the course of their disease, patients should be offered appropriate management options for treatment of incontinence, the mainstay of which is antimuscarinic medications, in combination, if necessary, with clean intermittent self-catheterisation. The evidence for other measures, including physiotherapy, alternative strategies aimed at improving bladder emptying, other medications and detrusor injections of botulinum toxin A was reviewed. The management of urinary tract infections as well as the bladder problems as part of severe disability were discussed and recommendations agreed.

A UK consensus on the management of the bladder in multiple sclerosis.

Bladder symptoms in multiple sclerosis (MS) are common and distressing but also highly amenable to treatment. A meeting of stakeholders involved in patients' continence care, including neurologists, urologists, primary care, MS nurses and nursing groups was recently convened to formulate a UK consensus for management. National Institute for Health and Clinical Excellence (NICE) criteria were used for producing recommendations based on a review of the literature and expert opinion. It was agreed that in the majority of cases, successful management could be based on a simple algorithm which includes using reagent sticks to test for urine infection and measurement of the post micturition residual urine volume. This is in contrast with published guidelines from other countries which recommend cystometry. Throughout the course of their disease, patients should be offered appropriate management options for treatment of incontinence, the mainstay of which is antimuscarinic medications, in combination, if necessary, with clean intermittent self-catheterisation. The evidence for other measures, including physiotherapy, alternative strategies aimed at improving bladder emptying, other medications and detrusor injections of botulinum toxin A was reviewed. The management of urinary tract infections as well as the bladder problems as part of severe disability were discussed and recommendations agreed.

Increased incidence of idiopathic persistent pulmonary hypertension in Down syndrome neonates.

Down syndrome (DS) patients have an increased risk of developing pulmonary hypertension later in life compared to age-matched controls. The goal of this study was to determine if the incidence of persistent pulmonary hypertension of the newborn (PPHN) is also higher in neonatal DS patients compared to the general population. A retrospective chart review of DS patients admitted during a 3-year period to the neonatal intensive care unit was performed. DS patients with meconium aspiration syndrome, pulmonary infections, or pulmonary space-occupying lesions were excluded. DS patients were divided into four groups based on treatment and consisted of no intervention (A), supplemental oxygen (B,) mechanical ventilation use (C), and inhaled nitric oxide administration (D). Group D was defined as having PPHN. z test of the difference between sample and known population, chi-square, t-test, and analysis of variance with Tukey adjusted post hoc test were used for analysis. p<0.05 was considered significant. A total of 58 patients met inclusion criteria. Twenty-four DS patients were in group A, 17 in group B, 10 in group C, and 7 in group D. There was no difference between the four groups for gender (males: 10, 5, 5, and 5, respectively), gestational age (36.4, 38.2, 36.4, and 36.4 weeks, respectively), weight (2.8, 3.0, 2.4, and 3.0 kg, respectively), or the presence of congenital heart defects (17, 10, 6, and 1, respectively). The estimated number of DS patients born in the state of Ohio during this period was 598; therefore, the incidence of PPHN in DS was 1.2%. The reported incidence of PPHN is 0.1%. The reported incidence of PPHN was significantly lower versus the incidence of PPHN in DS (z=2.7, p=0.007). It was concluded that DS patients have an increased incidence of PPHN compared to historical controls regardless of baseline demographics.

Arm and ankle blood pressure during caesarean section.

BACKGROUND: We have previously reported that measurement of non-invasive blood pressure during caesarean section under spinal anaesthesia fails in over 50% of cases. We felt that errors would be less likely if blood pressure could be measured at the ankle as it is immobile during caesarean section. The purpose of our study was to determine whether blood pressure measurement at the ankle was equivalent to the arm. METHOD: Following ethical approval, informed consent was obtained from 30 women scheduled for elective caesarean section. Two non-invasive blood pressure cuffs, one on the upper arm and one on the ankle, were used to measure blood pressures at three timed intervals: before spinal insertion, before surgery and after delivery of the neonate. RESULTS: Using the method of Bland and Altman we found that there was only marginal agreement between the two methods. On eight out of 15 occasions where there was a greater than 20% fall in arm systolic blood pressure, this was not detected at the ankle. CONCLUSION: We cannot recommend the use of the ankle to measure blood pressure during caesarean section.

Adult granulosa cell tumour of the testis and bony metastasis. A report of the first case of granulosa cell tumour of the testicle metastasising to bone.

Granulosa cell tumour is among the rarest forms of testicular cancer. Only 21 cases have been reported to date and only 4 have metastasised. All documented metastases are intra-abdominal. We present the first case of granulosa cell tumour of the testis metastasising to bone (tibia), presenting 6 years after orchidectomy. This highlights the need to maintain a high index of suspicion for extra-abdominal metastases during long-term follow-up in patients with previous testicular granulosa cell tumour.

Encapsulation of recombinant adenovirus into alginate microspheres circumvents vector-specific immune response.

Pre-existing immunity against adenoviruses may compromise the efficacy of adenoviral vectors for vaccination and gene therapy. The purpose of this study was to determine whether encapsulation of adenovirus recombinants into biodegradable alginate microparticles could circumvent the vector-specific immune response. Mice were immunized either intranasally (i.n.) or intraperitoneally (i.p.) with human adenovirus type 5 (HAd5), resulting in the development of virus-specific antibodies. Immunized and nai;ve mice were inoculated with AdCA36lacZ (an E1-deleted HAd5 recombinant containing the bacterial beta-galactosidase (LacZ) gene), encapsulated (E) into alginate microparticles, or nonencapsulated (NE) ie, as a virus suspension. LacZ expression in animals immunized once (1x) or twice (2x) with HAd5 and subsequently inoculated with NE-AdCA36lacZ (NE-Z) was significantly (P<0.001) reduced compared to those levels observed in NE-Z inoculated nai;ve mice, suggesting that the immune response against the vector adversely affected transgene expression. In contrast, there was only slight reduction (P>0.05) in LacZ expression in mice immunized 1x or 2x with HAd5 that were subsequently inoculated with E-AdCA36lacZ (E-Z) compared to those levels obtained in E-Z inoculated nai;ve animals. Similar results were obtained with i.n. or i.p. inoculated animals. These results indicate that microencapsulation of recombinant adenovirus effectively circumvented the vector-specific immune response.

Mice lacking desmocollin 1 show epidermal fragility accompanied by barrier defects and abnormal differentiation.

The desmosomal cadherin desmocollin (Dsc)1 is expressed in upper epidermis where strong adhesion is required. To investigate its role in vivo, we have genetically engineered mice with a targeted disruption in the Dsc1 gene. Soon after birth, null mice exhibit flaky skin and a striking punctate epidermal barrier defect. The epidermis is fragile, and acantholysis in the granular layer generates localized lesions, compromising skin barrier function. Neutrophils accumulate in the lesions and further degrade the tissue, causing sloughing (flaking) of lesional epidermis, but rapid wound healing prevents the formation of overt lesions. Null epidermis is hyperproliferative and overexpresses keratins 6 and 16, indicating abnormal differentiation. From 6 wk, null mice develop ulcerating lesions resembling chronic dermatitis. We speculate that ulceration occurs after acantholysis in the fragile epidermis because environmental insults are more stringent and wound healing is less rapid than in neonatal mice. This dermatitis is accompanied by localized hair loss associated with formation of utriculi and dermal cysts, denoting hair follicle degeneration. Possible resemblance of the lesions to human blistering diseases is discussed. These results show that Dsc1 is required for strong adhesion and barrier maintenance in epidermis and contributes to epidermal differentiation.

The lipocalin protein family: structural and sequence overview.

Lipocalins are remarkably diverse at the sequence level yet have highly conserved structures. Most lipocalins share three characteristic conserved sequence motifs - the kernel lipocalins - while others are more divergent family members - the outlier lipocalins - typically sharing only one or two. This classification is a useful tool for analysing the family, and within these large sets are smaller groups sharing much higher levels of sequence similarity. The lipocalins are also part of a larger protein superfamily: the calycins, which includes the fatty acid binding proteins, avidins, a group of metalloproteinase inhibitors, and triabin. The superfamily is characterised by a similar structure (a repeated +1 topology beta-barrel) and by the conservation of a remarkable structural signature.

Immunization with DNA, adenovirus or both in biodegradable alginate microspheres: effect of route of inoculation on immune response.

To determine the potential for biodegradable alginate microspheres to be used as a delivery vehicle for DNA based vaccines, we constructed a plasmid, pMNe-gal-SV40, containing the bacterial beta-galactosidase (LacZ) gene under the control of the murine cytomegalovirus (MCMV) immediate-early promoter and the simian virus 40 (SV40) polyadenylation signal. The effect of the route of administration and co-administration of adenovirus on systemic and mucosal immune responses were investigated. Mice were inoculated orally, intranasally (i.n.), intramuscularly (i.m.), subcutaneously (s.c.) or intraperitoneally (i.p.) on days 0, 14 and 28 with microspheres containing plasmid DNA, bovine adenovirus type 3 (BAd3) or plasmid DNA + BAd3. Systemic routes of immunization (i.m., s.c. and i.p.) resulted in higher LacZ- or BAd3-specific IgG ELISA titers compared to those obtained by mucosal routes of inoculation (oral and i.n.). Mucosal immunization led to slightly higher titers of LacZ- or BAd3-specific IgA at mucosal sites compared to those obtained by the various systemic routes. All the routes of immunization induced LacZ-specific lymphoproliferation. Co-administration of BAd3 enhanced the LacZ-specific IgG response irrespective of the route of administration.

Molecular map of the desmosomal plaque.

Recent biochemical and molecular approaches have begun to establish the protein interactions that lead to desmosome assembly. To determine whether these associations occur in native desmosomes we have performed ultrastructural localisation of specific domains of the major desmosomal components and have used the results to construct a molecular map of the desmosomal plaque. Antibodies directed against the amino- and carboxy-terminal domains of desmoplakin, plakoglobin and plakophilin 1, and against the carboxy-terminal domains of desmoglein 3, desmocollin 2a and desmocollin 2b, were used for immunogold labelling of ultrathin cryosections of bovine nasal epidermis. For each antibody, the mean distance of the gold particles, and thus the detected epitope, from the cytoplasmic surface of the plasma membrane was determined quantitatively. Results showed that: (i) plakophilin, although previously shown to bind intermediate filaments in vitro, is localised extremely close to the plasma membrane, rather than in the region where intermediate filaments are seen to insert into the desmosomal plaque; (ii) while the 'a' form of desmocollin overlaps with plakoglobin and desmoplakin, the shorter 'b' form may be spatially separated from them; (iii) desmoglein 3 extends across the entire outer plaque, beyond both desmocollins; (iv) the amino terminus of desmoplakin lies within the outer dense plaque and the carboxy terminus some 40 nm distant in the zone of intermediate filament attachment. This is consistent with a parallel arrangement of desmoplakin in dimers or higher order aggregates and with the predicted length of desmoplakin II, indicating that desmoplakin I may be folded or coiled. Thus several predictions from previous work were borne out by this study, but in other cases our observations yielded unexpected results. These results have significant implications relating to molecular interactions in desmosomes and emphasise the importance of applying multiple and complementary approaches to biological investigations.

Biodegradable alginate microspheres as a delivery system for naked DNA.

Sodium alginate is a naturally occurring polysaccharide that can easily be polymerized into a solid matrix to form microspheres. These biodegradable microspheres were used to encapsulate plasmid DNA containing the bacterial beta-galactosidase (LacZ) gene under the control of either the cytomegalovirus (CMV) immediate-early promoter or the Rous sarcoma virus (RSV) early promoter. Mice inoculated orally with microspheres containing plasmid DNA expressed LacZ in the intestine, spleen and liver. Inoculation of mice with microspheres containing both the plasmid DNA and bovine adenovirus type 3 (BAd3) resulted in a significant increase in LacZ expression compared to those inoculated with microspheres containing only the plasmid DNA. Our results suggest that adenoviruses are capable of augumenting transgene expression by plasmid DNA both in vitro and in vivo.

Hard alpha-keratin intermediate filament chains: substructure of the N- and C-terminal domains and the predicted structure and function of the C-terminal domains of type I and type II chains.

The quantity of sequence data now available for both Type I and Type II hard alpha-keratin IF proteins makes it possible to analyze their N- and C-terminal domains and ascertain features of likely structural and/or functional importance. The N-terminal domains of both chain types can be divided into acidic (NA) and basic (NB) subdomains, where NA is 29 and 34 residues long, respectively, for Type I and II chains and is located immediately adjacent to the end of the rod domain. NB constitutes the remainder of the N-terminal domain and is about 27 and 70 residues long for the two chain types, respectively. The glycine residue contents, however, are high in NA(I) and NB(II), but low in NA(II) and NB(I). Subdomain NB(II) contains four consecutive nonapeptide quasirepeats of the form GGGFGYRSX. The C-terminal domain of Type I chains, termed C(I), is characterized by a PCX motif repeated 10 times, 7 of them contiguously. From an analysis of the conformation of like peptides from crystal structures it has been shown that this region will probably adopt a polyproline II left-handed helical structure with three residues per turn. In contrast, the C-terminal domain of Type II hard alpha-keratin chains (known as C(II)) contains a periodic distribution of hydrophobicities that, together with other predictive techniques, allow its conformation (a twisted four-stranded antiparallel beta-sheet) to be predicted with some degree of confidence. In addition, it is possible to suggest two partners with which this domain will interact. The first is with segment L12 in the rod domain and the second is with another C(II) domain in an antiparallel neighboring molecule. The latter possibility appears most likely. In either case the aggregation would likely serve to stabilize the molecular assembly through the interaction of two beta-sheets via their apolar faces and, in so doing, would position a number of cysteine residues in external positions that would allow them to form a number of covalent disulfide bonds with other molecules.

Desmosomal adhesion inhibits invasive behavior.

Recent studies of human disease and transgenic animal experiments have clearly demonstrated the importance of desmosomes in normal tissue architecture. Furthermore, desmosomal components are down-regulated in certain types of carcinomas, suggesting a possible role for desmosomes in suppression of invasion and metastasis. However, there is no functional evidence to support such a hypothesis. To obtain such evidence, we needed to generate desmosomal adhesion in an invasive cell line. We show that expression of multiple desmosomal components (the desmosomal cadherins, desmocollin and desmoglein, and the armadillo protein, plakoglobin) in nonadhesive L929 fibroblasts generates adhesion in aggregation assays. This adhesion is specifically blocked by short peptides corresponding to the putative cell adhesion recognition sites of desmocollin and desmoglein. This result provides an experimental demonstration of the functional importance of the cell adhesion recognition sites of desmocollin and desmoglein and indicates that both desmosomal cadherins are specifically involved in this adhesion. Moreover, whereas parental L929 cells are strongly invasive into collagen gels, we show that invasion is substantially inhibited in cells transfected with desmosomal components. Invasion is restored by treating the transfected cells with anti-adhesion peptides, indicating that desmosomal adhesion specifically blocks invasion in culture. Our results support the suggestion that desmosomes have a role in suppression of tumor spreading.

Bovine beta-lactoglobulin at 1.8 A resolution--still an enigmatic lipocalin.

BACKGROUND: beta-Lactoglobulin (beta-Lg) is the major whey protein in the milk of ruminants and many other mammals. Its function is not known, but it undergoes at least two pH-dependent conformational changes which may be important. Bovine beta-Lg crystallizes in several different lattices, and medium-resolution structures of orthorhombic lattice Y and trigonal lattice Z have been published. Triclinic lattice X and lattice Z crystals grow at pH values either side of the pH at which one of the pH-induced conformational changes occurs. A full understanding of the structure is needed to help explain both the conformational changes and the different denaturation behaviour of the genetic variants. RESULTS: We have redetermined the structure of beta-Lg lattice Z at 3.0 A resolution by multiple isomorphous replacement and have partially refined it (R factor = 24.8%). Using the dimer from this lattice Z structure as a search model, the triclinic crystal form grown at pH 6.5 (lattice X) has been solved by molecular replacement. Refinement of lattice X at 1.8 A resolution gave an R factor of 18.1%. The structure we have determined differs from previously published structures in several ways. CONCLUSIONS: Incorrect threading of the sequence in the published structures of beta-Lg affects four of the nine beta strands. The basic lipocalin fold of the polypeptide chain is unchanged, however. The relative orientation of the monomers in the beta-Lg dimer differs in the two lattices. On raising the pH, there is a rotation of approximately 5 degrees, which breaks a number of intersubunit hydrogen bonds. It is not yet clear, however, why the stability of the structure should depend so heavily upon the external loop around residue 64 or the beta strand with the free thiol, each of which shows genetic variation.