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Within the first 4 months of the Western Australian COVID-19 immunisation program, 49 suspected anaphylaxis cases were reported to the vaccine safety surveillance system. Twelve reports met Brighton Collaboration case definition, corresponding to rates of 15.9 and 17.7 per million doses of Vaxzevria and Comirnaty administered, respectively. This article is protected by copyright. All rights reserved.

AIM Over two thirds of newborn deaths occur in Africa and South Asia, and respiratory failure is a major contributor of these deaths. The exact availability of continuous positive airway pressure (CPAP) and surfactant in Africa is unknown. The aim of this study was to describe the availability of newborn respiratory care treatments in the countries of Africa. METHODS Surveys, in English, French and Portuguese, were sent to neonatal leaders in all 48 continental countries and the two islands with populations over 1 million. RESULTS Forty-nine (98%) countries responded. Twenty-one countries reported less than 50 paediatricians, and 12 countries had no neonatologists. Speciality neonatal nursing was recognised in 57% of countries. Most units were able to provide supplemental oxygen. CPAP was available in 63% and 67% of the most well-equipped government and private hospitals. Surfactant was available in 33% and 39% of the most well-equipped public and private hospitals, respectively. Availability of CPAP and surfactant was greatly reduced in smaller cities. Continuous oxygen saturation monitoring was only available in 33% of countries. CONCLUSION The availability of proven life-saving interventions in Africa is inadequate. There is a need to sustainably improve availability and use of these interventions.

Gene fusions resulting from structural rearrangements are an established mechanism of tumorigenesis in pediatric cancer. In this clinical cohort, 1,350 single nucleotide polymorphism (SNP)-based chromosomal microarrays from 1,211 pediatric cancer patients were evaluated for copy number alterations (CNAs) associated with gene fusions. Karyotype or fluorescence in situ hybridization studies were performed in 42% of the patients. Ten percent of the bone marrow or solid tumor specimens had SNP array-associated CNAs suggestive of a gene fusion. Alterations involving ETV6, ABL1-NUP214, EBF1-PDGFRB, KMT2A(MLL), LMO2-RAG, MYH11-CBFB, NSD1-NUP98, PBX1, STIL-TAL1, ZNF384-TCF3, P2RY8-CRLF2, and RUNX1T1-RUNX1 fusions were detected in the bone marrow samples. The most common alteration among the low-grade gliomas was a 7q34 tandem duplication resulting in a KIAA1549-BRAF fusion. Additional fusions identified in the pediatric brain tumors included FAM131B-BRAF and RAF1-QKI. COL1A1-PDGFB, CRTC1-MAML2, EWSR1, HEY1, PAX3- and PAX7-FOXO1, and PLAG1 fusions were determined in a variety of solid tumors and a novel potential gene fusion, FGFR1-USP6, was detected in an aneurysmal bone cyst. The identification of these gene fusions was instrumental in tumor diagnosis. In contrast to hematologic and solid tumors in adults that are predominantly driven by mutations, the majority of hematologic and solid tumors in children are characterized by CNAs and gene fusions. Chromosomal microarray analysis is therefore a robust platform to identify diagnostic and prognostic markers in the clinical setting.

Background Patients frequently report antibiotic allergies; however, only 10% of labelled patients have a true allergy. Aim We investigated the documentation of antibiotic ‘allergy’ labels (AAL) and the effect of labelling on clinical outcomes, in a West Australian adult tertiary hospital. Methods Retrospective cross-sectional analysis of patients captured in the 2013 and 2014 National Antimicrobial Prescribing Surveys was carried out. Data were collected on documented antibiotic adverse drug reactions, antibiotic cost, prescribing appropriateness, prevalence of multi-drug resistant organisms, length of stay, intensive care admission and readmissions. Results Of the 687 patients surveyed, 278 (40%) were aged 70 or above, 365 (53%) were male and 279 (41%) were prescribed antibiotics. AAL were recorded in 122 (18%) patients and the majority were penicillin labels (n = 87; 71%). Details of AAL were documented for 80 of 141 (57%) individual allergy labels, with 61 describing allergic symptoms. Patients with beta-lactam allergy labels received fewer penicillins (P = 0.0002) and more aminoglycosides (P = 0.043) and metronidazole (P = 0.021) than patients without beta-lactam labels. Five patients received an antibiotic that was contraindicated according to their allergy status. Patients with AAL had significantly more hospital readmissions within 4 weeks (P = 0.001) and 6 months (P = 0.025) of discharge, compared with unlabelled patients. The majority (81%) of readmitted labelled patients had major infections. Conclusions AAL are common, but poorly documented in hospital records. Patients with AAL are significantly more likely to require alternative antibiotics and hospital readmissions. There may be a role for antibiotic allergy delabelling to mitigate the clinical and economic burdens for patients with invalid allergy labels.

Enzymes often use nucleophilic serine, threonine, and cysteine residues to achieve the same type of reaction; the underlying reasons for this are not understood. While bacterial d,d‐transpeptidases (penicillin‐binding proteins) employ a nucleophilic serine, l,d‐transpeptidases use a nucleophilic cysteine. The covalent complexes formed by l,d‐transpeptidases with some β‐lactam antibiotics undergo non‐hydrolytic fragmentation. This is not usually observed for penicillin‐binding proteins, or for the related serine β‐lactamases. Replacement of the nucleophilic serine of serine β‐lactamases with cysteine yields enzymes which fragment β‐lactams via a similar mechanism as the l,d‐transpeptidases, implying the different reaction outcomes are principally due to the formation of thioester versus ester intermediates. The results highlight fundamental differences in the reactivity of nucleophilic serine and cysteine enzymes, and imply new possibilities for the inhibition of nucleophilic enzymes.

β‐Lactamases threaten the clinical use of carbapenems, which are considered antibiotics of last resort. The classical mechanism of serine carbapenemase catalysis proceeds through hydrolysis of an acyl‐enzyme intermediate. We show that class D β‐lactamases also degrade clinically used 1β‐methyl‐substituted carbapenems through the unprecedented formation of a carbapenem‐derived β‐lactone. β‐Lactone formation results from nucleophilic attack of the carbapenem hydroxyethyl side chain on the ester carbonyl of the acyl‐enzyme intermediate. The carbapenem‐derived lactone products inhibit both serine β‐lactamases (particularly class D) and metallo‐β‐lactamases. These results define a new mechanism for the class D carbapenemases, in which a hydrolytic water molecule is not required.

The majority of pediatric low-grade gliomas (LGGs) are characterized by constitutive activation of the mitogen-activated protein kinase (MAPK) pathway through various mechanisms including BRAF mutations, inactivation of NF1, and KIAA1549-BRAF and FAM131B-BRAF fusions. The KIAA1549-BRAF fusion typically results from a 2.0 Mb tandem duplication in chromosome band 7q34. In the present study, single nucleotide polymorphism (SNP)-based array analysis of three LGGs demonstrated deletions in 7q34 that resulted in a BRAF fusion. Case 1 was likely a pilocytic astrocytoma (PA) with three deletions in 7q33q34 and an exon 15-9 KIAA1549-BRAF fusion. SNP array analysis of case 2, a possible dysembryoplastic neuroepithelial tumor (DNT), revealed a 2.6 Mb deletion, which included the 5' end of BRAF and extended to the 3' end of FAM131B. In case 3, deletions involving BRAF and FAM131B were observed in both a primary and a recurrent PA. RNA-based sequence analysis of cases 2 and 3 confirmed a fusion between FAM131B exon 2 and BRAF exon 9. The presence of fusion transcripts in these three LGGs highlights the utility of SNP array analysis to identify deletions that are suggestive of fusion proteins. BRAF fusions can result from multiple non-overlapping deletions, suggesting various complex mechanisms of formation.

In 22q11.2 deletion patients, the normal decrease in T lymphocyte counts after 1–2 years is blunted such that relatively T lymphocyte numbers increase over early childhood, probably via post-thymic expansion of peripheral lymphocytes. This may leave less T lymphocyte receptor (TCR) diversity than when derived from naive thymic emigrants. We analysed TCR Vβ repertoire on 27 22q11.2 chromosome deletion patients. No patient had infection at sampling. CD3+CD4+ recent thymic emigrants (RTEs) were identified by CD45RA and CD31 expression. TCR Vβ repertoire was determined using four-colour flow cytometry. Patients and controls showed significant TCR Vβ family usage differences between CD3+CD4+ and CD3+CD4− T lymphocyte subpopulations. Vβ family abnormalities (±3 SD of controls) were identified in 18/27 (67%) patients and 12/47 (25%) controls. In patients, the magnitude of expansions was increased, with some Vβ families representing 37% of the cells present in the subpopulations. There was a significant increase in frequency of abnormalities in CD3+CD4+ (P

Background—Germline mutations and deletions of SMARCB1/INI1 in chromosome band 22q11.2 predispose patients to rhabdoid tumor and schwannomatosis. Previous estimates suggested that 15–20% of rhabdoid tumors were caused by an underlying germline abnormality of SMARCB1. However, these studies were limited by case selection and an inability to detect intragenic deletions and duplications. Procedure—One hundred matched tumor and blood samples from patients with rhabdoid tumors of the brain, kidney, or soft tissues were analyzed for mutations and deletions of SMARCB1 by FISH, multiplex ligation-dependent probe amplification (MLPA), sequence analysis and high resolution Illumina 610K SNP based oligonucleotide array studies. Results—Thirty-five of 100 patients were found to have a germline SMARCB1 abnormality. These abnormalities included point and frameshift mutations, intragenic deletions and duplications, and larger deletions including regions both proximal and distal to SMARCB1. There were 9 cases that demonstrated parent to child transmission of a mutated copy of SMARCB1. In 8 of the 9 cases, one or more family members were also diagnosed with rhabdoid tumor or schwannoma, and 2 of the 8 families presented with multiple affected children in a manner consistent with gonadal mosaicism. Conclusions—Approximately one third of newly diagnosed patients with rhabdoid tumor have an underlying genetic predisposition to tumors due to a germline SMARCB1 alteration. Families may demonstrate incomplete penetrance and gonadal mosaicism, which must be considered when counseling families of patients with rhabdoid tumor.

Poly-L-proline has been used as a model system for various purposes over a period of more than 60 years. Its relevance among the protein/peptide community stems from its use as a reference system for determining the conformational distributions of unfolded peptides and proteins, its use as a molecular ruler, and from the pivotal role of proline residues in conformational transitions and protein–protein interactions. While several studies indicate that polyproline can aggregate and precipitate in aqueous solution, a systematic study of the aggregation process is still outstanding. We found, by means of UV-circular dichroism and IR measurements, that polyproline is predominately monomeric at room temperature at millimolar concentrations. Upon heating, the polypeptide stays in its monomeric state until the temperature reaches a threshold of ca. 60°C. At higher temperatures, the peptide aggregates as a film on the inside surface of the employed cuvette. The process proceeds on a time scale of 103 s and can best be described by a bi-exponential relaxation function. The respective CD and IR spectra are qualitatively different from the canonical spectra of polyproline in aqueous solution, and are indicative of a highly packed state. © 2009 Wiley Periodicals, Inc. Biopolymers 93: 451–457, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

A tin(IV) porphyrin was combined with two axial NCN-pincer platinum(II) fragments by utilizing the oxophilicity of the apical positions on the tin atom and the acidic nature of the NCN-pincer platinum derived benzoic acid. The solid-state structure determined by X-ray crystallography revealed some close contacts between the pincer complexes and the meso-p-tolyl subsitutents of the porphyrin. It was shown by 1H NMR spectroscopy that these close contacts were not present in solution and that this compound can potentially act as a novel building block for supramolecular architectures.

A series of meso-tetrakis- (ERE donor) zinc(II) porphyrins nZn (ERE donor = 4-R-3,5-bis((E)-methyl)- phenyl; 1Zn: E = NMe2 ,R = Br; 2Zn: E = NMe2 ,R = H; 3Zn: E = OMe, R = Br; 4Zn: E = OMe, R = H) have been synthesized in excellent yields. As a result of the combination of a Lewis acidic site and eight Lewis basic sites within one molecule, monomeric mole- cules of nZn self-assemble to form one-dimensional porphyrin polymers (nZn)1 in the solid state, as confirmed for 1Zn and 3Zn by X-ray crystallogra- phy. The coordination environment around the zinc(II) ions in these poly- mers is octahedral. They are ligated by four equatorial nitrogen atoms of the porphyrin and two apical E atoms (E = N, O) provided by the EBrE donor groups of adjacent nZn molecules. Complexes 2Zn and 4Zn did not form single crystals, but solid-state UV/Vis analysis points to the formation of sim- ilar structures. Solution UV/Vis and 1 H NMR spectroscopy indicated that interactions between 1Zn and 2Zn monomers in the polymers are stronger than between 3Zn and 4Zn monomers. Interestingly, they also revealed that the presence of a neighboring bromine atom in the EBrE donor groups has a considerable influence on the coordina- tion properties of the benzylic N or O atoms. The zinc(II) ions of the porphyr- ins most likely adopt only hexacoordi- nation in the solid state, owing to the unique predisposition of Lewis acidic and basic sites in the nZn molecules. Several parameters of the aggregates, for example, the interplanar separation between porphyrins and the zinc-zinc distances, change as a function of the coordinating E groups. The high degree of modularity in their synthesis makes these zinc(II) porphyrins an in- teresting new entry in noncovalent multiporphyrin assemblies.

22q11.2 deletion syndrome is the commonest chromosome deletion syndrome. 22q11.2 deletion may result in variable clinical phenotypes which may differ even between patients with identical deletions. Abnormal pharyngeal arch development results in defects in the development of the parathyroid glands, thymus and conotruncal region of the heart. Defective thymic development is associated with impaired immune function. ‘Complete’ DiGeorge syndrome with total absence of the thymus and a severe T-cell immunodeficiency accounts for

Sex hormones influence cardiovascular risk and bone mineral density. Total oestradiol is Increased in postmenopausal women with type 2 diabetes, whereas its impact on androgens, sex hormone binding globulin (SHBG) and gonadotrophins in postmenopausal women is not so clearly understood. This study aims to clarify the impact of type 2 diabetes on sex hormone levels in Caucasian postmenopausal women. Type 2 diabetic (n=42) and non-diabetic (n=45) postmenopausal women were recruited. Venous blood samples were drawn and, assayed for total testosterone, luteinising hormone (LH, follicle stimulating hormone (FSH) and SHBG. Ratio of total testosterone to SHBO was used as an index of free, testosterone(FT). Total oestradiol and FT were significantly higher in diabetic subjects compared to controls - oestradiol median: 59.5(25th, 75th centiles: 41.5, 74.5) vs 42.5(37.0, 59.8)pmol/L, p=0.009) Mann-Whitney test; and FT 0.038(0.021, 0.070) vs 0.022(0.012, 0.036), p=0.003. SHBG, FSH and LH were lower in diabetic subjects compared to controls - SHBG: 32(23.3,47.3) vs 55(37,70)nmol/L, p

A 21-year-old student developed an acute, symmetrical, predominantly motor polyneuropathy within 48 h of walking through a patch of nettles (Urtica ferox). Two companions had similar but less severe symptoms. Nerve conduction studies demonstrated markedly reduced compound muscle action potentials and prolonged distal motor latencies. Recovery occurred over a period of a few weeks. This case demonstrates that cutaneous exposure to Urtica ferox can cause an acute polyneuropathy and that its stinging hairs contain an unidentified neurotoxin.

* Floral meristems are generally determinate. Termination of their activity varies with species, occurring after carpel or ovule development, depending on the placentation type. In terminal flowering Impatiens balsamina (cv. Dwarf Bush Flowered) some flowers exhibit meristem indeterminacy; they produce organs from the placenta after ovule development. * Here we provide a detailed description of gynoecium development in this line and explore the basis of the indeterminate nature of some of its floral meristems. * We find that the placenta is sometimes established without complete carpel fusion. Proliferative growth derives from meristematic remnants of the placenta and is more common in the terminal inflorescence. RNA in situ hybridization reveals that IbLFY (Impatiens LFY homologue) is expressed in all meristem states, even in proliferating meristems. Expression of IbAG in axillary flowers is as expected in the meristem, stamens and carpels but absent from the proliferating meristem. * We conclude that I. balsamina has cauline placentation. Incomplete suppression of inflorescence identity in flowers of the terminal inflorescence leads to floral meristem proliferation after ovule development in this species.

In Impatiens balsamina a lack of commitment of the meristem during floral development leads to the continuous requirement for a leaf-derived floral signal. In the absence of this signal the meristem reverts to leaf production. Current models for Arabidopsis state that LEAFY (LFY) is central to the integration of floral signals and regulates flowering partly via interactions with TERMINAL FLOWER1 (TFL1) and AGAMOUS (AG). Here we describe Impatiens homologues of LFY, TFL1 and AG (IbLFY, IbTFL1 and IbAG) that are highly conserved at a sequence level and demonstrate homologous functions when expressed ectopically in transgenic Arabidopsis. We relate the expression patterns of IbTFL1 and IbAG to the control of terminal flowering and floral determinacy in Impatiens. IbTFL1 is involved in controlling the phase of the axillary meristems and is expressed in axillary shoots and axillary meristems which produce inflorescences, but not in axillary flowers. It is not involved in maintaining the terminal meristem in either an inflorescence or indeterminate state. Terminal flowering in Impatiens appears therefore to be controlled by a pathway that uses a different integration system than that regulating the development of axillary flowers and branches. The pattern of ovule production in Impatiens requires the meristem to be maintained after the production of carpels. Consistent with this morphological feature IbAG appears to specify stamen and carpel identity, but is not sufficient to specify meristem determinacy in Impatiens.

New nonsymmetric metallo(II)-salphen complexes 1–6 [salphen = N,N-bis(salicylidene)-1,2-diaminobenzene, M = Zn, Ni] have been prepared in high yield by a templated, one-pot two-step procedure starting from substituted orthophenylenediamines, salicylaldehydes and metal acetates in MeOH under mild conditions. The procedure allows the introduction of functional groups in the bridging phenyl fragment, whereas the use of the substituted monoimine intermediates 7–10 results in complexes with two structurally dif

Zn II -salphen complexes are readily accessible and interesting supramolecular building blocks with a large structural diversity. Higher-order supramolecular assemblies, such as mo- lecular boxes based on a bis-Zn II -sal- phen building block and various ditopic bipyridine ligands, have been construct- ed by means of supramolecular, coordi- native Zn II -Npyr interactions. The use of bipyridine ligands of differing sizes enables the construction of structures with predefined box diameters. The features of the 2:2 box assemblies were investigated in detail by (variable tem- perature) NMR spectroscopy, UV-visi- ble spectroscopy, NMR titrations, and X-ray crystallographic studies. The spectroscopic studies reveal a high as- sociation constant for the Zn II -sal- phen-pyridyl motif, which lies in the range 10 5 -10 6 m 1 . The strong interac- tion between the Zn II center and pyri- dine donors was supported by PM3 cal- culations that showed a relatively high Lewis acid character of the metal center in the salphen complex. Titra- tion curves monitored by UV-visible show a cooperative effect between the two bipyridine ligands upon complexa- tion to the bis-Zn II template, suggesting the formation of 2:2 complexes. The crystal structures of two supramolec- ular boxes have been determined. In both examples such a 2:2 assembly is present in the solid state, and the box size is different because they consist of different building blocks. Interestingly, the box assemblies line up in the solid state to form porous channels that are potentially useful in a number of appli

Aims Hormone replacement therapy (HRT) has been previously reported to modulate vascular function and cardiovascular risk. Its impact on the macrocirculation has previously been explored, however, little data is available on its impact on the microcirculation. This study aimed to determine the impact of HRT on microvascular function in healthy and Type 2 diabetic postmenopausal women (n = 20 and 17, respectively).Methods Microvascular function was assessed by skin maximum hyperaemia, skin hyperaemic response to iontophoretically applied acetylcholine (endothelial-dependent vasodilator) and sodium nitroprusside (endothelial-independent vasodilator), capillary pressure and the microvascular filtration capacity. Microvascular assessments were carried out at baseline and repeated following 6 months' oral hormone replacement therapy (1 mg oestradiol/0.5 mg norethisterone or 1 mg unopposed oestradiol for hysterectomized women).Results Following 6 months' therapy there were no significant changes in microvascular assessments in the healthy women. In the diabetic women there was a reduction in the skin hyperaemic response to acetylcholine [median pretreatment peak response: 1.95 (25th, 75th centiles: 1.54, 2.30) V vs. post-treatment peak response: 1.53 (1.30, 1.91) V (P = 0.011, Wilcoxon's signed rank test)] and sodium nitroprusside [median peak response 1.59 (1.37, 1.99) vs. 1.35 (0.92, 1.63) V (P = 0.011)] with HRT, but no other changes.Conclusion These data suggests that HRT does not affect microvascular function in healthy women, but adversely affects it in diabetic women. These findings may help to explain why HRT fails to provide the predicted cardiovascular protection, and raises the possibility that HRT influences microangiopathy progression in diabetic women.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by bone marrow (BM) failure, pancreatic insufficiency, and skeletal abnormalities. Mutations in the SBDS gene on chromosome arm 7q, explain 90% of SDS cases (Boocock et al, 2003). SBDS is essential for the assembly of mature ribosomes. Frequently SDS patients are compound heterozygotes for two common SBDS mutations (the 183_184 TA→CT and 258+2 T→C mutations). The null 183_184 TA→CT mutation results in a stop codon while the 258+2 T→C mutation causes a splicing error with only small amounts of full length protein produced (Austin et al, 2005). Homozygosity for the 183_184 TA→CT mutation has never been found. Here we describe acquired copy number neutral loss of heterozygosity (CN-LOH) for most of 7q in an SDS patient. The clone of BM cells with CN-LOH contained 2 copies of the gene with the 258+2 T→C mutation, which increases the level of SBDS protein providing the likely explanation for clonal expansion of the affected haematopoietic progenitor cell. Neutropenia was found in a neonatal female when a complete blood count was performed due to concerns of neonatal sepsis. In addition to haematological and infectious issues, this patient also developed exocrine pancreatic insufficiency. At four months of age she was diagnosed with SDS, which was confirmed by gene sequencing. A BM aspiration and biopsy were performed on the patient at 13 months of age and a follow-up examination was performed a year later. Karyotypes were prepared, and single nucleotide polymorphism (SNP) analysis of DNA isolated from the BM aspirates was accomplished with the HumanHap610 (first BM) or Omni1-Quad (second BM aspirate) genotyping beadchip (Illumina, San Diego, CA). The patient and her unaffected parents were recruited for a research study at the Children's Hospital of Philadelphia, Pennsylvania, USA. Samples from skin, BM and peripheral blood (PB) from the patient as well as PB from the parents were obtained after written informed consent. The Ethics Committee of the Hospital approved the study in accordance with the declaration of Helsinki. SNP analysis of DNA from the parents PB was performed with the Illumina Human Omni1-Quad gene chip. Data analysis was performed with GenomeStudio Software (Illumina). Plots of two parameters, the log2R ratio and the B allele frequency, provided information regarding copy number and genotype. The comparison between the genotype data of the parents and the CN-LOH region in the patient was performed with GenomeStudio Software. Polymerase chain reaction and Sanger sequencing of BM DNA and DNA from cultured skin fibroblasts and PB was carried out by standard procedures (Boocock et al, 2003, Sanger and Coulson 1975). The BM aspirate and biopsy performed on the patient at 13 months of age, showed normal cellularity, with normal erythropoiesis and megakaryopoiesis, with a decrease in myeloid progenitors. Standard cytogenetic analysis revealed a normal karyotype 46,XX. Genome wide (GW) SNP array analysis revealed CN-LOH in 20% of the cells from a region just below the centromere of chromosome 7 to the end of 7q (Figure 1). A similar percentage of cells with 7q CN-LOH and no other cytogenetic abnormalities were identified on a second BM one year later. Figure 1 B allele frequency results and LOH analysis from BM of CHOP256.01 at chromosome 7 Genotype analysis of the parents showed that the mother was heterozygous for the 183_184 TA→CT mutation and the father was heterozygous for the 258+2 T→C mutation. The patient was heterozygous for both mutations. Analysis of 683 informative markers from 7q showed that the LOH was due to loss of the maternal alleles. The comparison of the 258+2 T→C sequencing peaks between fibroblast and BM samples from the patient showed that the 258+2 C peak was slightly higher than the 258+2 T peak in the BM sample but not in the skin sample (Figure 2). These results indicate that the cells with LOH of 7q detected in the BM of the patient have two copies of the SBDS 258+2 T→C mutation. Figure 2 Chromatograph of the SBSD 258+2 T→C mutation from BM(A) and skin (B) Our results are consistent with clonal expansion of cells, in the BM of an SDS patient, that have undergone a genetic event producing LOH for 7q, including the SBDS gene. Genetic analysis shows that the expanded clone contains 2 copies of the hypomorphic SBDS mutation while the constitutional genotype is compound heterozygous for 258+2 T→C and 183_184 TA→CT. This is the third example of somatic genomic changes leading to clonal expansion in the BM of SDS patients. Clonal cytogenetic abnormalities affecting 7q have been repeatedly observed in the BM of SDS patients (Dror et al, 2002, Shimamura 2006, Smith et al, 2002). The most frequent is an isochromosome 7q (i(7)(q10)), leading to 3 copies of 7q. Interestingly, all of the compound heterozygous SDS patients with i(7)(q10) clones analysed so far have an extra copy of the 258+2 T→C mutated gene (Minelli et al, 2009). In those cases, as in the case described here, there is an increase in the copy number of the gene producing some active protein. Another common cytogenetic event in SDS is an interstitial deletion in 20q removing a region that includes the EIF6 gene (Pressato et al, 2012). It was recently shown that SBDS couples with the GTPase EFL1 to cause the release of EIF6 from the pre-60S ribosome subunit, an essential step in the formation of the mature ribosome (Finch et al, 2011). It was hypothesized that the decreased amount of EIF6 in these cells, in the context of SBDS deficiency, improved ribosome biogenesis. Again the deletion is associated with clonal expansion. Interestingly SDS has an increased likelihood of progression to myelodysplastic syndrome/acute myeloid leukaemia that is frequently associated with numerical and structural chromosome 7 anomalies. To the contrary, both i(7)(q10) and the 20q deletion in patients with SDS are associated with low risk of transformation of the affected cell clone (Minelli et al, 2009, Pressato, et al, 2012), though this relationship has been questioned (Dror et al, 2002). Interestingly this patient is another example of an emerging paradigm whereby, in the context of the aplastic BM, haematopoietic progenitor cells that partially overcome the disease causing genetic lesion due to acquired genomic changes have a survival or growth advantage, leading to clonal expansion. Somatic genomic changes and clonal expansion have been observed in other BM failure syndromes (May 2011). These changes often improve blood cell production and in some cases decrease the risk of leukaemic transformation. Such “natural gene therapy” may be instructive concerning possible drug targets.

Advances in reproductive medicine have significantly increased the success of fertility treatments. Nevertheless, some women experience recurrent implantation failure (RIF) after in-vitro fertilization (IVF) or recurrent pregnancy loss (RPL). Imbalances in the immune system and failure to achieve immune tolerance to the foetus have been implicated as potentially modifiable causes of idiopathic RIF and RPL. As such, women are increasingly being treated with immunomodulatory agents in an attempt to achieve a successful pregnancy. This systematic review examines the published evidence on immune changes in these patients, the use of immunomodulation therapies and diagnostic testing modalities to guide their use or to identify patient subsets most likely to benefit. The PubMed database was searched for the terms "recurrent implantation failure" and "recurrent pregnancy loss" in conjunction with T-helper (Th) cells and their subsets in particular; Th1, Th2, Th17 and T-regulatory (Treg) cells, natural killer (NK) cells, cytokine imbalance as well as immune modulators and immune suppressants. The reference lists of articles were examined to identify additional articles. There remains limited data on the immunological changes in cytokine and cellular profiles during the hormonal cycle as well as prior to, during and after implantation in health as well as idiopathic RIF and RPL. There is a need to advance immunological diagnostics to match the clinical need in this emerging field and to guide clinicians to make optimal and safe therapeutic choices. It is also imperative that the well-being of the infants conceived after such intervention is monitored.