Case Report: Congenital Radioulnar Synostosis and Its Embryological Correlation and Functional Assessment

Congenital radioulnar synostosis(CRS) is a rare anomaly and approximately 400 cases were reported worldwide so far. CRS is the failure of the longitudinal segmentation and the persistence of the cartilaginous anlage between the radius and ulna during the seventh week of development that results in a persistent bridge of tissue. Here we are discussing on a case of 25yrs old, male patient with bilateral congenital synostosis. On the left hand the pronation and supination movements are restricted completely where as on right side 10 degree of supination and 20 degree of pronation is possible. Radiologically in our patient synostosis is classified as type II variety by Wilkie(1914)1 classification and type IV by the Cleary and Omer classification(1985). The position of forearm was not found to be related to subjective functional limitation, or employment status. Main line of treatment is surgical mainly rotational osteotomy but is rarely indicated. Our patient is not able to rotate his forearm especially on the left side still he has no functional limitation so he has refused for the operative treatment. No study has objectively compared the preoperative functional limitation of the patients with their postoperative functional improvement in order to justify surgical intervention In the authors opinion the only major factor that is to be taken into consideration of operative treatment is functional limitation to the patient.     

Evaluation of the introduction of a standardised protocol for the staging and follow-up of colorectal cancer on resection rates for liver metastases

INTRODUCTION

In 2004, an audit in our unit demonstrated wide variation in liver resection rates for colorectal cancer (CRC) metastases within the cancer network. Subsequently, a network-wide CT-based follow-up and referral policy was introduced for all patients. A second audit was performed to assess the impact of the guidelines on liver resection rates.

SUBJECTS AND METHODS

Analysis of prospective liver resection database between 1997 and 2004 and after the introduction of standardised guidelines between January 2005 and April 2008.

RESULTS

A total of 362 patients underwent liver resection for CRC metastases between 1997 and 2008, 237 prior to the introduction of the referral guidelines and 125 after. Liver resection rates according to referring hospital varied from 0.92 to 2.32 per 100,000 population before guidelines were introduced. After 2005, resection rates from the four district hospitals standardised (1.68–1.84 per 100,000 population), but the central unit rate (Sheffield) remained significantly higher (2.67 per 100,000 population). No significant difference in 1-year disease-free survival between patients from Sheffield and the outlying hospitals was found (P = 0.553).

CONCLUSIONS

Introduction of a referral protocol standardised resection rates from the four district hospitals, but these remain lower compared to the specialist centre. The wide-spread adoption of a policy to discuss all patients with liver metastases at an advanced disease multidisciplinary team meeting, in the presence of hepatobiliary specialists, may further increase resection rates across the UK.     

Assessment of the quality of reference books on botanical dietary supplements

OBJECTIVE: To review books on botanical dietary supplements (BDS) targeted to pharmacists and physicians to assess their overall quality as primary and secondary reference books. DESIGN: We purchased 52 books for initial review based primarily on their titles. After eliminating books not written for health care professionals and books that contained very limited information on BDS, we selected 22 texts to review in depth. PARTICIPANTS: The review team consisted of four pharmacists--two with PhDs in pharmacognosy, one with a PhD in pharmaceutics, and one with a PharmD who is a senior medical student. RESULTS: The authors, reviewers, and editors of some books were highly qualified; others lacked the qualifications to summarize scientific information in a balanced, unbiased manner. Many books contain unsubstantiated statements. The books judged to be of the highest quality provide primary references to support all statements and advise the reader that insufficient information is available to assess potential drug interactions and safety during pregnancy and lactation. CONCLUSION: The quality of the information presented in the reviewed books varies dramatically. The most critical information gaps include the potential for drug interactions and the safe use of specific botanicals during pregnancy and lactation.     

Causality and functional relevance of BRCA1 and BRCA2 pathogenic variants in non-high-grade serous ovarian carcinomas

The identification of causal BRCA1/2 pathogenic variants (PVs) in epithelial ovarian carcinoma (EOC) aids the selection of patients for genetic counselling and treatment decision-making. Current recommendations therefore stress sequencing of all EOCs, regardless of histotype. Although it is recognised that BRCA1/2 PVs cluster in high-grade serous ovarian carcinomas (HGSOC), this view is largely unsubstantiated by detailed analysis. Here, we aimed to analyse the results of BRCA1/2 tumour sequencing in a centrally revised, consecutive, prospective series including all EOC histotypes. Sequencing of n = 946 EOCs revealed BRCA1/2 PVs in 125 samples (13%), only eight of which were found in non-HGSOC histotypes. Specifically, BRCA1/2 PVs were identified in high-grade endometrioid (3/20; 15%), low-grade endometrioid (1/40; 2.5%), low-grade serous (3/67; 4.5%), and clear cell (1/64; 1.6%) EOCs. No PVs were identified in any mucinous ovarian carcinomas tested. By re-evaluation and using loss of heterozygosity and homologous recombination deficiency analyses, we then assessed: (1) whether the eight ‘anomalous’ cases were potentially histologically misclassified and (2) whether the identified variants were likely causal in carcinogenesis. The first ‘anomalous’ non-HGSOC with a BRCA1/2 PV proved to be a misdiagnosed HGSOC. Next, germline BRCA2 variants, found in two p53-abnormal high-grade endometrioid tumours, showed substantial evidence supporting causality. One additional, likely causal variant, found in a p53-wildtype low-grade serous ovarian carcinoma, was of somatic origin. The remaining cases showed retention of the BRCA1/2 wildtype allele, suggestive of non-causal secondary passenger variants. We conclude that likely causal BRCA1/2 variants are present in high-grade endometrioid tumours but are absent from the other EOC histotypes tested. Although the findings require validation, these results seem to justify a transition from universal to histotype-directed sequencing. Furthermore, in-depth functional analysis of tumours harbouring BRCA1/2 variants combined with detailed revision of cancer histotypes can serve as a model in other BRCA1/2-related cancers. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.     

Antigen persistence and the control of local T cell memory by migrant respiratory dendritic cells after acute virus infection

Acute viral infections induce robust adaptive immune responses resulting in virus clearance. Recent evidence suggests that there may be depots of viral antigen that persist in draining lymph nodes (DLNs) after virus clearance and could, therefore, affect the adaptive immune response and memory T cell formation. The nature of these residual antigen depots, the mechanism of antigen persistence, and the impact of the persistent antigen on memory T cells remain ill defined. Using a mouse model of influenza virus infection of the respiratory tract, we identified respiratory dendritic cells (RDCs) as essential for both sampling and presenting residual viral antigen. RDCs in the previously infected lung capture residual viral antigen deposited in an irradiation-resistant cell type. RDCs then transport the viral antigen to the LNs draining the site of infection, where they present the antigen to T cells. Lastly, we document preferential localization of memory T cells to the DLNs after virus clearance as a consequence of presentation of residual viral antigen by the migrant RDC.The induction of the adaptive immune response to an infectious agent consists of a defined series of events prompted by invasion of the body by the organism, followed by replication of the organism and the subsequent initiation of an innate and adaptive immune response. For organisms that enter at a body surface and confine replication primarily to that site, for example, infection of the respiratory tract by seasonal type A influenza, innate responses are triggered by infection of cells at the body surfaces and activation of sentinel innate immune cells in the surrounding tissues. Induction of the adaptive immune response typically requires the uptake/infection by the organism or uptake of its constituents by tissue-resident professional APCs, most notably immature DCs (Banchereau and Steinman, 1998; Lambrecht et al., 2001; de Heer et al., 2005). These professional APCs transport the organism or its products to secondary lymphoid organs, usually LNs draining the site of infection (draining LN [DLN]) where adaptive immune (T and B cells) responses are initiated. In the case of experimental mouse influenza infection, at least two distinct subsets of respiratory DCs (RDCs) have been implicated as critical APCs in the induction of primary T cell responses to this virus (GeurtsvanKessel et al., 2008; Kim and Braciale, 2009).The outcome of the interaction between an invading microorganism and the immune system is either clearance of the agent or the development of chronic persistent infection. Viruses such as HIV, HCV, and, in the mouse model, LCMV, can produce chronic persistent infection with high titers of the virus because of the ability of these viruses to subvert or suppress the host immune response (Ahmed et al., 1984; Bevan and Braciale, 1995; Letvin and Walker, 2003; Wherry et al., 2003; Rehermann and Nascimbeni, 2005). Persistence of viral antigen at high levels in these infections may contribute to the dysregulation of the adaptive immune response observed in these infections (Shin and Wherry, 2007). In contrast, acute infection with many viruses results in rapid virus clearance (even with an initial high level of virus replication) and, presumably, elimination of virus-infected cells by the action of the adaptive and innate immune response.Recently, however, evidence has emerged to suggest that after acute viral infection viral antigen can be detectable for an extended period, i.e., weeks to months, after clearance of infectious virus. This phenomenon is not only observed with viruses capable of establishing persistent infection in vitro, for example, respiratory syncytial virus (RSV; P’ringle et al., 1978; Schwarze et al., 2004) and Sendai virus (Mori et al., 1995), but has also been observed for classically lytic viruses, such as type A influenza (Jelley-Gibbs et al., 2005; Zammit et al., 2006) and VSV (Turner et al., 2007), which are not believed to produce chronic persistent infection of cells. In these instances, viral antigen was detected using the proliferative response of adoptively transferred TCR transgenic (Tg) T cells into previously infected animals as a sensitive measure of antigen persistence. Although the nature and the mechanism of antigen persistence in these instances was not defined, several studies provided evidence that the presentation of this residual viral antigen to T cells may influence the quality of the memory T cell response to infection (Jelley-Gibbs et al., 2005, 2007; Zammit et al., 2006; Turner et al., 2007; Woodland and Kohlmeier, 2009).In several studies reporting persistence of viral antigen after acute infection and subsequent virus clearance, the reservoir of antigen (as detected by adoptive transfer of virus-specific T cells) was localized within secondary lymphoid organs, most notably the LN draining the site of infection (Jelley-Gibbs et al., 2005, 2007; Zammit et al., 2006). In this paper, we describe a series of experiments to investigate the underlying mechanism of the persistence of antigen presentation after respiratory tract infection with type A influenza virus. We found that a reservoir of viral antigen (i.e., RNA and protein) is present for an extended period after an acute influenza virus infection at the site of infection (i.e., the lungs) and localized to both nonhematopoietic (CD45⁻) and hematopoietic (CD45⁺) cell types within residual mild lung inflammatory foci. We further demonstrate that the residual viral antigen deposited in the previously infected lung is captured and transported by RDC to the regional LN, where the migrant RDC function in presenting the residual antigen to T cells. In addition, we provide evidence that lung follicular DCs (FDCs) may play an important role in regulating the response of RDC. Finally, our results suggest that as a consequence of presentation of residual viral antigen by the migrant RDC to T cells in the LNs draining the site of infection, there is preferential localization of memory T cells to the DLN after virus clearance. The implications of these observations are discussed.     

Dietary genistein increased DMBA-induced mammary adenocarcinoma in wild-type, but not ER alpha KO, mice.

Dietary supplements containing concentrates of plant-derived estrogens are being increasingly used by consumers as alternatives for hormone replacement therapy, for treatment of menopausal symptoms, and as cancer preventives. The effect of dietary genistein on dimethylbenz[a]anthracene (DMBA)-induced mammary tumor development was investigated in wild-type (ER alpha WT) and estrogen receptor-alpha knockout (ER alpha KO) mice. ER alpha WT and ER alpha KO mice were fed a casein-based diet containing 0 or 1 g genistein/kg diet from weaning. Tumors were induced by oral administration of DMBA and subscapular implantation of medroxyprogesterone acetate. No tumors were observed in ER alpha KO mice. In ER alpha WT mice, dietary intake of genistein influenced tumor development, enhancing anaplasia of mammary cancer. Mice consuming genistein expressed malignant mammary adenocarcinoma, whereas benign adenomas were observed in mice fed the control diet. Dietary intake was also influenced by genistein, with ER alpha WT and ER alpha KO mice fed genistein consuming less food (p < 0.0001) and subsequently weighing less than mice fed the control diet (p < 0.0001). Significant differences in food intake by genotype were also observed (p = 0.0017), with ER alpha KO mice consuming less than ER alpha WT mice. Overall, this study found no protective effect of genistein on DMBA-induced mammary tumors in mice and suggests a potential adverse effect on tumor development when high levels of genistein are consumed.