Rapid response to abatacept in treatment-resistant pansclerotic morphoea.

Morphoea is a spectrum of disorders characterized by inflammation and sclerosis of the skin and potentially underlying tissues. There are no specific licensed treatments for morphoea and prospective studies on commonly used therapies are lacking. We describe a case of progressive, recalcitrant pansclerotic morphoea with a rapid response to abatacept.

New Zealand's extinct giant raptor (Hieraaetus moorei) killed like an eagle, ate like a condor.

The extinct Haast's eagle or harpagornis (Hieraaetus moorei) is the largest known eagle. Historically, it was first considered a predator, then a scavenger, but most recent authors have favoured an active hunting ecology. However, the veracity of proposed similarities to carrion feeders has not been thoroughly tested. To infer feeding capability and behaviour in harpagornis, we used geometric morphometric and finite-element analyses to assess the shape and biomechanical strength of its neurocranium, beak and talons in comparison to five extant scavenging and predatory birds. The neurocranium of harpagornis is vulture-like in shape whereas its beak is eagle-like. The mechanical performance of harpagornis is closer to extant eagles under biting loads but is closest to the Andean condor (Vultur gryphus) under extrinsic loads simulating prey capture and killing. The talons, however, are eagle-like and even for a bird of its size, able to withstand extremely high loads. Results are consistent with the proposition that, unlike living eagles, harpagornis habitually killed prey larger than itself, then applied feeding methods typical of vultures to feed on the large carcasses. Decoupling of the relationship between neurocranium and beak shape may have been linked to rapid evolution.

Pulmonary arterial hypertension - progress in understanding the disease and prioritizing strategies for drug development.

Pulmonary arterial hypertension (PAH), at one time a largely overlooked disease, is now the subject of intense study in many academic and biotech groups. The availability of new treatments has increased awareness of the condition. This in turn has driven a change in the demographics of PAH, with an increase in the mean age at diagnosis. The diagnosis of PAH in more elderly patients has highlighted the need for careful phenotyping of patients and for further studies to understand how best to manage pulmonary hypertension associated with, for example, left heart disease. The breadth and depth of expertise focused on unravelling the molecular pathology of PAH has yielded novel insights, including the role of growth factors, inflammation and metabolic remodelling. The description of the genetic architecture of PAH is accelerating in parallel, with novel variants, such as those reported in potassium two-pore domain channel subfamily K member 3 (KCNK3), adding to the list of more established mutations in genes associated with bone morphogenetic protein receptor type 2 (BMPR2) signalling. These insights have supported a paradigm shift in treatment strategies away from simply addressing the imbalance of vasoactive mediators observed in PAH towards tackling more directly the structural remodelling of the pulmonary vasculature. Here, we summarize the changing clinical and molecular landscape of PAH. We highlight novel drug therapies that are in various stages of clinical development, targeting for example cell proliferation, metabolic, inflammatory/immune and BMPR2 dysfunction, and the challenges around developing these treatments. We argue that advances in the treatment of PAH will come through deep molecular phenotyping with the integration of clinical, genomic, transcriptomic, proteomic and metabolomic information in large populations of patients through international collaboration. This approach provides the best opportunity for identifying key signalling pathways, both as potential drug targets and as biomarkers for patient selection. The expectation is that together these will enable the prioritization of potential therapies in development and the evolution of personalized medicine for PAH.

Egg shape mimicry in parasitic cuckoos.

Parasitic cuckoos lay their eggs in nests of host species. Rejection of cuckoo eggs by hosts has led to the evolution of egg mimicry by cuckoos, whereby their eggs mimic the colour and pattern of their host eggs to avoid egg recognition and rejection. There is also evidence of mimicry in egg size in some cuckoo-host systems, but currently it is unknown whether cuckoos can also mimic the egg shape of their hosts. In this study, we test whether there is evidence of mimicry in egg form (shape and size) in three species of Australian cuckoos: the fan-tailed cuckoo Cacomantis flabelliformis, which exploits dome nesting hosts, the brush cuckoo Cacomantis variolosus, which exploits both dome and cup nesting hosts, and the pallid cuckoo Cuculus pallidus, which exploits cup nesting hosts. We found evidence of size mimicry and, for the first time, evidence of egg shape mimicry in two Australian cuckoo species (pallid cuckoo and brush cuckoo). Moreover, cuckoo-host egg similarity was higher for hosts with open nests than for hosts with closed nests. This finding fits well with theory, as it has been suggested that hosts with closed nests have more difficulty recognizing parasitic eggs than open nests, have lower rejection rates and thus exert lower selection for mimicry in cuckoos. This is the first evidence of mimicry in egg shape in a cuckoo-host system, suggesting that mimicry at different levels (size, shape, colour pattern) is evolving in concert. We also confirm the existence of egg size mimicry in cuckoo-host systems.

Comparison of minimally invasive parathyroidectomy under local anaesthesia and minimally invasive video-assisted parathyroidectomy for primary hyperparathyroidism: a cost analysis.

BACKGROUND: Primary hyperparathyroidism (PHPT) origins from a solitary adenoma in 70- 95% of cases. Moreover, the advances in methods for localizing an abnormal parathyroid gland made minimally invasive techniques more prominent. This study presents a micro-cost analysis of two parathyroidectomy techniques. PATIENTS AND METHODS: 72 consecutive patients who underwent minimally invasive parathyroidectomy, video-assisted (MIVAP, group A, 52 patients) or "open" under local anaesthesia (OMIP, group B, 20 patients) for PHPT were reviewed. Operating room, consumable, anaesthesia, maintenance costs, equipment depreciation and surgeons/anaesthesiologists fees were evaluated. The patient's satisfaction and the rate of conversion to conventional parathyroidectomy were investigated. T-Student's, Kolmogorov-Smirnov tests and Odds Ratio were used for statistical analysis. RESULTS: 1 patient of the group A and 2 of the group B were excluded from the cost analysis because of the conversion to the conventional technique. Concerning the remnant patients, the overall average costs were: for Operative Room, 1186,69 € for the MIVAP group (51 patients) and 836,11 € for the OMIP group (p<0,001); for the Team, 122,93 € (group A) and 90,02 € (group B) (p<0,001); the other operative costs were 1388,32 € (group A) and 928,23 € (group B) (p<0,001). The patient's satisfaction was very strongly in favour of the group B (Odds Ratio 20,5 with a 95% confidence interval). CONCLUSIONS: MIVAP is more expensive compared to the "open" parathyroidectomy under local anaesthesia due to the costs of general anaesthesia and the longer operative time. Moreover, the patients generally prefer the local anaesthesia. Nevertheless, the rate of conversion to the conventional parathyroidectomy was relevant in the group of the local anaesthesia compared to the MIVAP, since the latter allows a four-gland exploration.

The coexistence of primary hyperparathyroidism and thyroid nodules: should the preoperative work-up of the parathyroid and the thyroid diseases be specifically adjusted?

INTRODUCTION AND OBJECTIVES: Primary hyperparathyroidism (PHPT) can be found in concomitance with thyroid disease (TD) in a high frequency of cases. In this context the diagnostic exams for localizing the enlarged parathyroid(s) gland(s) could be less reliable or nonconclusive. Moreover, the thyroid carcinoma seems to be more frequent compared to that isolated thyroid desease and, therefore, carefully investigated. The main goal of the present study is to evaluate which diagnostic tool (US, MIBI) is more reliable for localizing the site of the PTH hypersecretion and to confirm if it is always advantageous a combination of both exams. Besides, we evaluated the incidence of thyroid carcinoma in our series of patients. PATIENTS AND METHODS: A review of available data of 73 patients who underwent total thyroidectomy + parathyroidectomy from 2003 and 2014 was performed. The preoperative workup included systematically US and MIBI whose results were considered true positive when at least the side (left/right) of the parathyroid affected were concordant with the surgical report, settled as the gold standard, according to the Cox nonnested model. The connection between the diagnostic results of US versus MIBI was calculated with the Cohen K index for evaluating their overlap. The average of the thyroid carcinoma were also calculated. RESULTS: The difference between respectively US versus surgical report (p value=0.73) and MIBI versus surgical report (p value=0.81) were not significant. The low Cohen K index showed that both US and MIBI are complementary. In 23 patients (32,9%) a thyroid carcinoma was found. CONCLUSIONS: The association of MIBI and neck US is mandatory in the first evaluation of patients undergoing thyroidectomy and parathyroid excision simultaneously. The high prevalence of thyroid carcinoma in this specific context suggests a more aggressive diagnostic and surgical behaviour.

A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis.

Nephropathic cystinosis, an autosomal recessive disorder resulting from defective lysosomal transport of cystine, is the most common inherited cause of renal Fanconi syndrome. The cystinosis gene has been mapped to chromosome 17p13. We found that the locus D17S829 was homozygously deleted in 23 out of 70 patients, and identified a novel gene, CTNS, which mapped to the deletion interval. CTNS encodes an integral membrane protein, cystinosin, with features of a lysosomal membrane protein. Eleven different mutations, all predicted to cause loss of function of the protein, were found to segregate with the disorder.

Protection of ovarian tissue from radiotherapy.

Advances researches in the diagnosis and treatment of childhood, adolescent and adult cancer have greatly increased the life expectancy of premenopausal women with cancer. However, one of the serious side effects of these treatments is the risk of damage to fertility. The ovaries are very sensitive to cytotoxic and radiotherapeutic treatment. The only established method of fertility preservation is embryo cryopreservation according to the Ethics Committee of the American Society for Reproductive Medicine (2005), but this option requires the patient to be of pubertal age, have a partner or use donor sperm, and be able to undergo a cycle of ovarian stimulation, which is not possible when the radiotherapy has to be initiated immediately or when stimulation is contraindicated according to the type of cancer. For patients who need immediate radiotherapy, cryopreservation of ovarian tissue is the only possible alternative. This manuscript reports the different techniques of cryopreservation and the results of transplantation of cryopreserved ovarian tissue. The current techniques allow cryopreservation of human ovarian fragments for a long time with good follicular survival rate after thawing. Numerous studies ultimately in this field have demonstrated to improve the survival rate of the oocytes and cryopreserved follicles. Moreover this manuscript includes a case of a 17-year-old girl who had to undergo pelvic irradiation for non-Hodgkin's lymphoma and the laparoscopic treatment to preserve the fertility (Fig. 2, Ref. 47).

Locally unresectable differentiated thyroid cancer: outcomes and perspectives.

PURPOSE: Differentiated thyroid cancer (DTC) patients with an unresectable primary tumor cannot benefit from curative surgery, and radioiodine treatment for locoregional and distant disease is not possible with the thyroid gland still in place. Due to local invasion, these patients cannot be included in clinical trials, so that treatment options are limited. The aim of this study was to describe the characteristics and the prognosis of patients with these locally unresectable DTC. PATIENTS AND METHODS: A retrospective and multicentric analysis of consecutive cases of unresectable DTC diagnosed between 2000 and 2015 was performed. RESULTS: The study population consisted in 22 patients, 13 females (59%); median age: 77 years (range: 52-91). Thyroid tumors were papillary in six, follicular in seven, Hürthle cell in one and poorly differentiated in eight patients. Patients were treated with external beam radiation therapy (EBRT) (57%), locoregional therapy of distant metastases (41%), cytotoxic chemotherapy (38%) and tyrosine kinase inhibitors (TKIs) (33%). TKI treatment resulted in median disease control duration of 7 months with a grade 3-4 toxicity rate of 44%. Only one patient had a total thyroidectomy after neo-adjuvant EBRT. The 1, 3 and 5-year cumulative survival rate was 81%, 27.7% and 21.5%, respectively. The cause of death was DTC in 11 cases (local progression in 7), and to other causes in 7 cases; no patient died from treatment toxicity. CONCLUSIONS: Clinical trials and approved treatments are lacking for unresectable DTC. TKI treatment may allow prolonged disease control with acceptable toxicity.

BRAF(V600E) mutation and the biology of papillary thyroid cancer.

BRAF((V600E)) mutation is the most frequent genetic alteration in papillary thyroid carcinomas (PTCs) that are 80-90% of all thyroid cancers. We evaluated the relationship between BRAF((V600E)) and tumor, host, and environmental factors in PTCs from all geographical areas of Sicily. By PCR, BRAF((V600E)) was investigated in a series of 323 PTCs diagnosed in 2002-2005. The correlation between clinicopathological tumor, host, and environmental characteristics and the presence of BRAF((V600E)) were evaluated by both univariate and multivariate analyses. BRAF((V600E)) was found in 38.6% PTCs, with a 52% frequency in the classical PTCs and 26.4% in the tall cell variant. Univariate analysis indicated that BRAF((V600E)) was associated with greater tumor size (P=0.0048), extra-thyroid invasion (P<0.0001), and cervical lymph nodal metastases (P=0.0001). Multivariate logistic regression analysis confirmed that BRAF((V600E)) was an independent predictor of extra-thyroid invasion (P=0.0001) and cervical lymph nodal metastasis (P=0.0005). The association between BRAF((V600E)) and extra-thyroid invasion was also found in micro-PTCs (P=0.006). In 60 classical PTCs, BRAF((V600E)) was positively correlated with matrix metalloproteinase-9 expression (P=0.0047), suggesting a possible mechanism for BRAF((V600E)) effect on PTC invasiveness. No association was found between BRAF((V600E)) and patient age, gender, or iodine intake. In contrast, a strong association was found with residency in Eastern Sicily (P<0.0001 compared with Western Sicily). These results indicate that BRAF((V600E)) mutation is a marker of aggressive disease in both micro- and macro-PTCs. Moreover, for the first time, a possible link between BRAF((V600E)) mutation and environmental carcinogens is suggested.

Variable kappa gene rearrangement in lymphoproliferative disorders: an analysis of V kappa gene usage, VJ joining and somatic mutation.

We have studied a diverse group of lymphoproliferative disorders (acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL), non-Hodgkin lymphoma (NHL) and myeloma) to determine if V kappa gene use is random or disease-specific and whether somatic mutations (a late event in B-cell differentiation) can provide additional information on the type of B cell involved in the neoplastic clone. In this group of disorders V kappa gene selection is not random and some members of each V kappa family are preferentially rearranged. V kappa genes from the distal portion of the locus are seldom used, possibly because rearrangement of the proximal locus by deletion is more efficient than rearrangement of the distal locus by inversion. Although pseudogenes account for 46% of the V genes in the kappa locus none were ever rearranged, even in non-functional rearrangements of lambda-producing leukemias, suggesting the existence of a mechanism which down-regulates the rearrangement of pseudogenes. N regions were noted at the VJ junction in 20% of alleles (in six CLL, three NHL, two ALL and one myeloma) possibly the result of kappa-chain recombination during the early period of B-cell maturation in which TdT is expressed. Nucleotide addition or imprecise joining at the VJ junction, resulting in a shift in the reading frame, were the commonest causes of non-functional rearrangement. The occurrence of somatic mutation broadly correlated with the stage of B-cell maturation from which the different disorders are thought to arise. However, there was no strict association and somatic mutations were demonstrated in 'typical CLL' while V kappa genes were germline in some follicular lymphomas; these findings suggest either heterogeneity in the stage of B-cell maturation at which these disorders arise or some variability in the process of somatic mutation.

Color Doppler measurement of blood flow in the inferior thyroid artery in patients with autoimmune thyroid diseases.

PURPOSE: The aim of the study is to find out whether the measurement of peak systolic velocity in the inferior thyroid artery (ITA) is a valuable parameter to differentiate autoimmune thyroid diseases (hyper-, normo- or hypofunctional) and to evaluate the efficacy of medical treatment. MATERIAL AND METHODS: The ITA of 31 patients (eight with Graves' disease, 23 with subclinical hypothyroidism) was examined with color Doppler and pulsed Doppler. The final diagnosis was obtained by cytology and by hormonal and antibodies assays. The patients were monitorized by ultrasound for a period of 8 months. RESULTS: In all the patients with Graves' disease the peak systolic velocity was always over 150 cm/s, while in other autoimmune thyroiditis the peak systolic velocity was within the normal range, and never exceeding 65 cm/s. In the first group, the measurement taken in the ITA showed also the efficacy of the pharmacological treatment earlier and more reliably than the color Doppler pattern obtained in the parenchyma. CONCLUSIONS: The color Doppler measurement of the ITA seems to be a promising technique with low-cost and easy approach. In our experience, the color Doppler of the ITA could have a clinical role in the differential diagnosis of diffuse thyroid diseases and in the follow-up of the Graves' disease during medical treatment.

Age-specific standardized mortality rates in people with learning disability.

The aim of the present study was to calculate the age-and sex-specific standardized mortality ratios (SMRs) in two populations of people with learning disability (LD). These populations included people living in institutions and community settings. It was found that SMRs tended to be raised for both males and females in each population, but SMRs do not always significantly differ from unity. For the combined Register populations, SMRs are generally significantly greater than unity. We conclude that these data provide evidence that death rates for people with LD are often higher than in the general population.

Prolactin-steroid influences on the thermal basis for mother-young contact in Norway rats.

Norway rat dams have a chronic elevation in core temperature throughout the first 2 wk postpartum, a situation that makes them vulnerable to a further, acute rise in body temperature during contact with their young. Prolactin appears to contribute to the chronic elevation of maternal temperature, probably by stimulating the secretion of progesterone, which then elevates the maternal thermal set point.

Impaired tongue strength and endurance in developmental verbal dyspraxia: a physiological analysis.

Tongue strength and endurance measures were obtained from six children with developmental verbal dyspraxia (DVD) aged between 5;6 years and 11;5 years and compared to those achieved by six normal speaking controls matched for age and sex. The instrument for measuring tongue strength comprised an air-filled soft rubber bulb connected to a pressure transducer. The results indicated that the DVD group had weaker lingual musculature than the controls. In addition the DVD subjects exhibited significantly reduced tongue strength endurance compared with the controls. Overall the findings support the hypothesis that a motor impairment forms at least part of the basis of DVD and may be indicative of the presence of a concomitant dysarthria in children with DVD, or may reflect an underspecification of the motor programme. The need for revision of contemporary taxonomies relating to childhood motor speech disorders is discussed.

Examination for platelet-activating factor production by preimplantation mouse embryos using a specific radioimmunoassay.

A specific and highly sensitive radioimmunoassay was used to measure platelet-activating factor (PAF) production by preimplantation mouse embryos in vitro. Levels of PAF greater than 1 pg per embryo were not observed in 24-h culture medium from 2-cell embryos, compacted morulae or blastocysts, or in extracts from these embryos. Synthetic PAF added to embryos at the start of culture could be almost totally recovered after the incubation period, indicating negligible degradation of PAF during culture. PAF was also not detected in embryo samples using a washed rabbit-platelet aggregation assay. It can be concluded that mouse embryos do not produce substantial levels of PAF, or any of the biologically active analogues of PAF detected by the assay.

Mortality in people with learning disability: risks, causes, and death certification findings in London.

Two thousand people with learning disabilities registered as service users in two London districts were followed up for 8 years to ascertain, in those who died, age and cause of death and significant associations with early death. Respiratory disease was documented as the leading cause of death in 52% of the study population compared with only 15% of males and 17% of females in the whole population. People with learning disabilities have an increased risk of early death. Although the majority of deaths (83%) in the whole population occur in people aged 65 years and over, less than 50% of deaths in the study population were in this age group, and the risk of dying before the age of 50 was 58 times higher than in England and Wales generally. Early death was significantly associated with cerebral palsy, incontinence, problems with mobility, and residence in hospital. Death certificates were not found to be a reliable source of data about factors contributing to cause of death, and learning disabilities were rarely mentioned. The authors recommend an extension to the current format of the Medical Certificate of Death to include recording of chronic disabling conditions.

Structure of the human sarco/endoplasmic reticulum Ca2+-ATPase 3 gene. Promoter analysis and alternative splicing of the SERCA3 pre-mRNA.

Human chromosome 17-specific genomic clones extending over 90 kilobases (kb) of DNA and coding for sarco/endoplasmic reticulum Ca2+-ATPase 3 (SERCA3) were isolated. The presence of the D17S1828 genetic marker in the cosmid contig enabled us to map the SERCA3 gene (ATP2A3) 11 centimorgans from the top of the short arm p of chromosome 17, in the vicinity of the cystinosis gene locus. The SERCA3 gene contains 22 exons spread over 50 kb of genomic DNA. The exon/intron boundaries are well conserved between human SERCA3 and SERCA1 genes, except for the junction between exons 8 and 9 which is found in the SERCA1 gene but not in SERCA3 and SERCA2 genes. The transcription start site (+1) is located 152 nucleotides (nt) upstream of the AUG codon. The 5'-flanking region, including exon 1, is embedded in a 1.5-kb CpG island and is characterized by the absence of a TATA box and by the presence of 14 putative Sp1 sites, 11 CACCC boxes, 5 AP-2-binding motifs, 3 GGCTGGGG motifs, 3 CANNTG boxes, a GATA motif, as well as single sites for Ets-1, c-Myc, and TFIIIc. Functional promoter analysis indicated that the GC-rich region (87% G + C) from -135 to -31 is of critical importance in initiating SERCA3 gene transcription in Jurkat cells. Exon 21 (human, 101 base pairs; mouse, 86 base pairs) can be alternatively excluded, partially included, or totally included, thus generating, respectively, SERCA3a (human and mouse, 999 amino acids (aa)), SERCA3b (human, 1043 aa; mouse, 1038 aa), or SERCA3c (human, 1024 aa; mouse, 1021 aa) isoforms with different C termini. Expression of the mouse SERCA3 isoforms in COS-1 cells demonstrated their ability to function as active pumps, although with different apparent affinities for Ca2+.

Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin.

Infantile nephropathic cystinosis is a rare, autosomal recessive disease caused by a defect in the transport of cystine across the lysosomal membrane and characterized by early onset of renal proximal tubular dysfunction. Late-onset cystinosis, a rarer form of the disorder, is characterized by onset of symptoms between 12 and 15 years of age. We previously characterized the cystinosis gene, CTNS, and identified pathogenic mutations in patients with infantile nephropathic cystinosis, including a common, approximately 65 kb deletion which encompasses exons 1-10. Structure predictions suggested that the gene product, cystinosin, is a novel integral lysosomal membrane protein. We now examine the predicted effect of mutations on this model of cystinosin. In this study, we screened patients with infantile nephropathic cystinosis, those with late-onset cystinosis and patients whose phenotype does not fit the classical definitions. We found 23 different mutations in CTNS; 14 are novel mutations. Out of 25 patients with infantile nephropathic cystinosis, 12 have two severely truncating mutations, which is consistent with a loss of functional protein, and 13 have missense or in-frame deletions, which would result in disruption of transmembrane domains and loss of protein function. Mutations found in two late-onset patients affect functionally unimportant regions of cystinosin, which accounts for their milder phenotype. For three patients, the age of onset of cystinosis was <7 years but the course of the disease was milder than the infantile nephropathic form. This suggests that the missense mutations found in these individuals allow production of functional protein and may also indicate regions of cystinosin which are not functionally important.