Obstetric anal sphincter injury by maternal origin and length of residence: a nationwide cohort study.

OBJECTIVE: To estimate the association between maternal origin and obstetric anal sphincter injury (OASI), and assess if associations differed by length of residence. DESIGN: Population-based cohort study. SETTING: The Medical Birth Registry of Norway. POPULATION: Primiparous women with vaginal livebirth of a singleton cephalic fetus between 2008 and 2017 (n = 188 658). METHODS: Multivariable logistic regression models estimated adjusted odds ratios (aORs) for OASI with 95% CI by maternal region of origin and birthplace. We stratified models on length of residence and paternal birthplace. MAIN OUTCOME MEASURES: OASI. RESULTS: Overall, 6373 cases of OASI were identified (3.4% of total cohort). Women from South Asia were most likely to experience OASI (6.2%; aOR 2.24, 95% CI 1.87-2.69), followed by those from Southeast Asia, East Asia & the Pacific (5.7%; 1.59, 1.37-1.83) and Sub-Saharan Africa (5.2%; 1.85, 1.55-2.20), compared with women originating from Norway. Among women born in the same region, those with short length of residence in Norway (0-4 years), showed the highest odds of OASI. Migrant women across most regions of origin had the lowest risk of OASI if they had a Norwegian partner. CONCLUSIONS: Primiparous women from Asian regions and Sub-Saharan Africa had up to two-fold risk of OASI, compared with women originating from Norway. Migrants with short residence and those with a foreign-born partner had higher risk of OASI, implying that some of the risk differential is due to sociocultural factors. Some migrants, especially new arrivals, may benefit from special attention during labour to reduce morbidity and achieve equitable outcomes. TWEETABLE ABSTRACT: Anal sphincter injury during birth is more common among Asian and Sub-Saharan migrants and particularly among recent arrivals.

Adjuvant taxanes and the development of breast cancer-related arm lymphoedema.

BACKGROUND: Despite affecting approximately one-quarter of all patients undergoing axillary lymph node dissection, the pathophysiology of breast cancer-related lymphoedema (BCRL) remains poorly understood. More extensive locoregional treatment and higher body mass index have long been identified as major risk factors. This study aimed to identify risk factors for BCRL with a specific focus on the potential impact of chemotherapy on the risk of BCRL. METHODS: This was a retrospective analysis of a cohort of consecutive patients with breast cancer treated at a major London regional teaching hospital between 1 January 2010 and 31 December 2012. All patients had node-positive disease and underwent axillary lymph node dissection. Data regarding tumour-, patient- and treatment-related characteristics were collected prospectively. The diagnosis of BCRL was based on both subjective and objective criteria. Multivariable Cox proportional hazards regression was used to assess the association between treatment and risk of BCRL. RESULTS: Some 27.1 per cent of all patients (74 of 273) developed BCRL over the study period. Administration of taxanes showed a strong association with the development of BCRL, as 52 (33.5 per cent) of 155 patients who received taxanes developed BCRL. Multivariable Cox regression analysis demonstrated that patients who received taxanes were nearly three times more likely to develop BCRL than patients who had no chemotherapy (hazard ratio 2.82, 95 per cent c.i. 1.31 to 6.06). No such increase was observed when taxanes were administered in the neoadjuvant setting. CONCLUSION: The present findings suggest that adjuvant taxanes play a key role in the development of BCRL after surgery. This may support the use of taxanes in a neoadjuvant rather than adjuvant setting.

Global abnormalities in lymphatic function following systemic therapy in patients with breast cancer.

BACKGROUND: Breast cancer-related lymphoedema (BCRL) is a result of interaction between several pathophysiological processes, and is not simply a 'stopcock' effect resulting from removal of axillary lymph nodes. The aim of this study was to test the hypothesis that there is a constitutional 'global' lymphatic dysfunction in patients who develop BCRL. METHODS: Lower-limb lymphoscintigraphy was performed in 30 women who had undergone axillary lymph node dissection at least 3 years previously, of whom 15 had BCRL and 15 did not. No patient had any clinical abnormality of the lower limb. The control group comprised 24 women with no history of cancer or lower-limb lymphoedema. (99m) Tc-Nanocoll was injected subcutaneously into the first webspace of each foot, followed by whole-body imaging. Scans were reported as abnormal if there was delay in lymph transport or rerouting through skin or deep system. Quantification was expressed as the percentage injected activity accumulating in ilioinguinal nodes. RESULTS: Mean(s.d.) ilioinguinal nodal accumulation at 150 min was significantly lower in women with BCRL than in those without (2·7(2·5) versus 5·9(4·8) per cent respectively; P = 0·006). Abnormal findings on lower-limb lymphoscintigraphy were observed in 17 of the 30 patients: ten of the 15 women who had BCRL and seven of the 15 who did not. None of the 24 control subjects had abnormal scan findings. CONCLUSION: Women with BCRL had reduced lower-limb lymph drainage, supporting the hypothesis of a predisposition to BCRL. A surprisingly high proportion of patients with breast cancer also demonstrated lymphatic dysfunction, despite clinically normal lower limbs. Possible explanations could be a systemic effect of breast cancer or its treatment, or an unidentified association between breast cancer and lymphatic dysfunction. REGISTRATION NUMBER: ISRCTN84866416 ( http://www.isrctn.com).

A novel assay to diagnose hereditary angioedema utilizing inhibition of bradykinin-forming enzymes.

BACKGROUND: Hereditary angioedema types I and II are caused by a functional deficiency of C1 inhibitor (C1-INH), leading to overproduction of bradykinin. The current functional diagnostic assays employ inhibition of activated C1s; however, an alternative, more physiologic method is desirable. METHODS: ELISAs were developed using biotinylated activated factor XII (factor XIIa) or biotinylated kallikrein bound to avidin-coated plates. Incubation with plasma was followed by detection of bound C1-INH. RESULTS: After standard curves were developed for quantification of C1-INH, serial dilutions of normal plasma were employed to validate the ability to detect known concentration of C1-INH in the plasma as a percent of normal. Hereditary angioedema (HAE) types I and II were then tested. The level of functional C1-INH in all HAE types I and II plasma tested was less than 40% of our normal control. This was evident regardless of whether we measured factor XIIa-C1-INH or kallikrein-C1-INH complexes, and the two assays were in close agreement. By contrast, testing the same samples utilizing the commercial method (complex ELISA, Quidel Corp.) revealed the levels of C1-INH between 0 and 57% of normal (mean, 38%), and 42 samples were considered equivocal (four controls and 38 patients). CONCLUSIONS: Diagnosis of HAE types I and II can be ascertained by inhibition of enzymes of the bradykinin-forming cascade, namely factor XIIa and kallikrein. Either method yields functional C1-INH levels in patients with HAE (types I and II) that are clearly abnormal with less variance or uncertainty than the commercial method.

Distribution and Characteristics of Congenital Cardiac Surgery Centers within Bangladesh.

Congenital heart disease is a leading cause of non-communicable childhood death. This is especially true in nations with limited resources where shortages of skilled workforce, healthcare facilities, and essential equipment limit the ability to provide care. This retrospective study was designed to determine the volume and distribution of surgical care being provided to patients with congenital heart disease in Bangladesh, as well as to characterize the facilities providing such care. Pre-existing survey data of hospitals performing congenital heart surgery in the year 2022 in Bangladesh was obtained. Additional information was gathered on these facilities, including hospital location and type. The distribution of care by geographic location, type of facility, and volume of cases was reported. Overall, a total of 2333 surgeries were performed in 2022 at 28 facilities. The majority of hospitals were performing <50 cases per year, while a small number (5) provided greater than 50.0% of all surgeries. In addition, while the majority of hospitals were private in nature, the majority of surgeries occurred at not-for-profit hospitals. There was a large geographic skew of surgeries and hospitals being located within the city of Dhaka (79.0% of centers and 94.0% of surgeries). The data suggests that, though there has been great progress in increasing the number of surgeries performed in Bangladesh, the vast majority of patients still do not have access to care. In addition, nearly all care is being provided in Dhaka, which presents challenges for patients who come from across the nation seeking care. Finally, there is a great need for further research to fully understand the challenges faced and find workable solutions.

Cancer and mental health--a clinical and research unmet need.

BACKGROUND: Poor mental health is the largest single source of disability in the UK, and co-morbid health problems, particularly with cancer, raise total health care costs significantly. METHODS: This study examined what research is being conducted into the intersection between cancer and mental health. Research papers captured by the intersection of sub-field filters-'mental disorder' and 'cancer'-were studied from the Web of Science over a 10-year period (2002-2011). RESULTS: There were 1463 papers dealing with the dual presence of cancer and mental disorder. They amounted to 0.26% of cancer research and 0.51% of mental health research over the 10-year period, indicating that their intersection receives little research attention. Eighty per cent of papers were concerned with the effects of cancer on mental health rather than the reverse; a few (5%) looked at the post-traumatic stress suffered by carers of cancer patients. Of cancer types, breast dominated (21%), followed by prostate (5%), lung (3%), oral (2%) and colorectal (2%) cancer. The area of mental health most studied in cancer was unipolar depression. CONCLUSIONS: The paucity of research that exists at the intersection of cancer and mental health requires attention from policymakers and funders in order to address an important trans-disciplinary gap in health care research.

Loss of caveolin-1 from bronchial epithelial cells and monocytes in human subjects with asthma.

BACKGROUND: Caveolin-1 has emerged as a critical regulator of signaling pathways involved in lung fibrosis and inflammation. METHODS: Therefore, we investigated whether caveolin-1 is deficient in asthmatic patients and in a murine model of asthma. RESULTS: Immunohistochemical analyses of endobronchial biopsies showed a remarkable loss of caveolin-1 in the lungs of asthmatic patients compared with controls. This loss was most evident in bronchial epithelial cells and associated with an increase in the expression of extracellular matrix proteins: collagen I, tenascin, and periostin. Cultured primary bronchial epithelial cells of asthmatics had lower caveolin-1 expression compared with control cells. In addition, caveolin-1 expression was significantly decreased in peripheral blood monocytes from asthma patients. The loss of caveolin-1 was also observed in a mouse model for asthma (mice sensitized and challenged with aspergillus fumigatus). CONCLUSIONS: To our knowledge, this is the first demonstration that the regulatory protein caveolin-1 is reduced in patients with asthma.

Identification of clinically relevant cross-sensitization between Soliadgo virgaurea (goldenrod) and Hevea brasiliensis (natural rubber latex).

BACKGROUND: Solidago virgaurea (goldenrod) is a perennial weed from which no allergens have been identified. A high latex content in its leaves has been reported. Although not an airborne allergen, it may be an important occupational sensitizer. OBJECTIVE: To identify allergenic proteins in goldenrod and to determine whether they cross-react with Hevea brasiliensis latex. METHODS: Potential cross-reactive allergens in latex and goldenrod were investigated by immunoblot inhibition and ImmunoCAP inhibition analyses using serum from patients with clinically evident goldenrod and/or latex allergy. Cross reactivity between latex allergens and goldenrod proteins was studied using recombinant Hev b 1, 3, 4, 5, 6.01, 6.02, 8, 9, or 11 in ImmunoCAP inhibition analyses. RESULTS: Immunoglobulin (Ig) E antibodies from individuals with goldenrod allergy bound extracted goldenrod proteins ranging from 20 kDa to 130 kDa in Western blots. Evidence for latex and goldenrod cross reactivity was identified by ImmunoCAP and immunoblot inhibition experiments using serum from patients with strongly positive concomitant latex and goldenrod-specific IgE antibody responses. Observed latex-goldenrod cross reactivity could not be ascribed to any of the recombinant major latex allergens evaluated. CONCLUSIONS: H brasiliensis latex and goldenrod contain cross-reactive and unique allergenic proteins. Exposure to goldenrod may sensitize patients to latex and vice versa.

An observational cohort study of the management and outcomes of vascular trauma.

OBJECTIVES: To evaluate aetiology, presentation, management and mortality following iatrogenic and non-iatrogenic vascular trauma in a regional vascular centre. METHODS: Retrospective observational cohort study of patients presenting with vascular trauma during a seven year period between January 2000 and December 2006. RESULTS: 182 cases of vascular trauma were identified (averaging 26 cases p.a.). The majority (n=132, 73%) were iatrogenic and tended to occur in patients aged >45 years, while 50 (27%) were penetrating/blunt, non-iatrogenic and predominantly occurred in younger males. The majority of iatrogenic vascular injuries (80/132) (61%) followed a cardiac intervention (angiography n=56, angioplasty n=23, pacemaker insertion n=1) and are now increasingly treated by non-operative therapies (thrombin, coils and covered stents). Overall, non-iatrogenic vascular trauma was associated with 4% mortality, compared with 7% following iatrogenic injury. However, while iatrogenic trauma of cardiological origin was associated with a mortality of only 1.3% (1/80), iatrogenic trauma of non-cardiological origin incurred a mortality of 17% (9/52). CONCLUSIONS: The commonest cause of vascular trauma (and with the lowest mortality rate) was cardiological related iatrogenic injury. However, while non-cardiological iatrogenic injury occurred with the same incidence as penetrating/blunt trauma, it was associated with a fourfold excess mortality.

A case of toxic megacolon in a patient with collagenous colitis.

Collagenous colitis is an uncommon inflammatory bowel disease, the aetiology of which is unknown. We report a case of toxic megacolon in a patient with collagenous colitis, a previously unreported complication.

Unilateral lower limb swelling secondary to cavernous lymphangioma.

INTRODUCTION: We report an unusual case of unilateral leg swelling secondary to cavernous lymphangioma (cystic hygroma), which normally affects the head and neck regions. CASE REPORT: A 25 year gentleman presented to our department with a 13-year history of gradually increasing unilateral leg swelling and recurrent infections. Investigations showed appearances consistent with cavernous lymphangioma, and partial excision of the lesion led to resolution of symptoms. DISCUSSION: The most common sites for cystic hygroma are the head and neck areas, but the extremities can be affected as demonstrated. Complete surgical excision is often difficult, and there is a tendency for recurrence. This case acts as an illustration of an uncommon yet important cause for unilateral leg swelling.

The doctors in training committee: a mechanism for change?

Medical engagement is increasingly important in ensuring that organizations deliver safe and effective patient care. The recent wave of encouragement for junior doctors to become 'change agents' is fundamental to embedding this culture. However, the mechanisms by which junior doctors engage in complex health-care systems are not well developed. The authors describe the process of setting up a doctors in training committee and its role in a large NHS trust as a way of improving junior doctor engagement.

The mouse t-complex gene, Tcp-11, is under translational control.

The mouse t-complex is known to harbour genes which affect male fertility. Tcp-11 is a t-complex gene which is only expressed in male germ cells and from its position is a candidate for a distorter, one of the two types of genetic element involved in transmission ratio distortion. Antibodies raised to TCP-11 protein made in E. Coli were used on thin sections of testis and shown to recognise late spermatids. On Western blots the antibodies bound to a 68-kD protein present in protein extracts from testis. No specific signal could be detected using the antibody on protein extracts from other mouse tissues. Following gentle lysis of the germ cells and fractionation on sucrose gradients, all the material recognised by the anti-Tcp-11 antibody was found to be soluble and unassociated with any membrane fraction or organelle. A comparison of the time course of expression of the Tcp-11 mRNA and the TCP-11 protein revealed that expression of this gene is under translational control.

Mitochondria control of cell death induced by anti-HLA-DR antibodies.

We have previously reported that crosslinking HLA-DR directly induces programmed cell death of malignant B cells. The present study further characterizes the biochemical mechanism for HLA-DR-mediated programmed cell death of tumor cells. Phosphatidylserine exposure on the plasma membrane and propidium iodide incorporation occur with very rapid kinetics and are observed as early as 10 min after the induction of cell death with anti-HLA-DR. In striking contrast to anti-CD95, we observe no activation of caspase-3, -8, or -9 upon anti-HLA-DR addition. Furthermore, the irreversible caspase inhibitor Z-VAD.fmk also failed to inhibit anti-HLA-DR-mediated cell death, further supporting the conclusion that HLA-DR induces cell death via a caspase-independent mechanism. We demonstrate that anti-HLA-DR-induced cell death is instead associated with a rapid disruption of the inner mitochondrial transmembrane potential, DeltaPsi(m), a process that is significantly inhibited by Bcl-2 overexpression. Furthermore, we find that DeltaPsi(m) disruption results in the selective release of apoptosis-inducing factor (AIF) from the mitochondria. We propose that AIF is acting to initiate the morphological and biochemical changes observed in HLA-DR-mediated cell death.

An investigation of lymphovenous communications in the upper limbs of breast cancer patients.

BACKGROUND: Approximately 25% of breast cancer patients who undergo treatment to the axilla develop breast cancer-related lymphoedema (BCRL). The aim of this study was to test the hypothesis that lymphovenous communications (LVCs) open and act as a protective mechanism against the development of BCRL. METHODS: Five patients (Group 1) received intradermal injections of (99m)Technetium-labelled autologous erythrocytes into the 2nd ipsilateral hand webspace before and 6-12 weeks following axillary node clearance surgery (ANC). Ten patients at least three years after ANC were also recruited (Group 2); seven had developed BCRL and three had not. Blood was sampled from ipsilateral and contralateral antecubital veins 5, 15, 30, 60, 120 and 180 min post-injection to assess pre-nodal shunting from lymph to blood (LVCs), since nodes block erythrocyte transit. The proportion of activity remaining in the depot was used to calculate the degree of shunting in those with evidence of LVCs. RESULTS: Significant erythrocyte-bound activity, increasing over time, was detected contralaterally in 3 of the 5 patients from Group 1 (none of whom developed BCRL) and 3 of 7 patients with BCRL from Group 2, which indicated the presence of LVCs. The degree of shunting was more marked in those patients who did not develop BCRL compared with those who did. CONCLUSIONS: The time-course of erythrocyte-bound contralateral activity indicates transit through lymphovenous communications rather than needle-induced trauma. Lymphovenous communications large enough to transmit erythrocytes are probably constitutional rather than induced. A larger study is warranted to assess any resulting protection against BCRL.

A constitutional predisposition to breast cancer-related lymphoedema and effect of axillary lymph node surgery on forearm muscle lymph flow.

AIM: The aims of this prospective study were (a) to examine the relationship between pre-operative muscle lymph flow and the predisposition to BCRL in women treated by axillary nodal surgery for breast cancer; and (b) to test the 'stopcock' hypothesis that axillary lymph node surgery impairs forearm lymph flow in the short term. METHODS: (99m)Tc-nanocoll was injected intramuscularly into both forearms of women undergoing surgery for breast cancer. Lymphatic clearance rate constant, k, representing lymph flow per unit interstitial fluid volume, was measured as the fractional disappearance rate of radioactivity from the depot site by gamma camera imaging. Axillary lymph node activity was calculated as percentage injected activity. BCRL was assessed by clinical examination and upper limb perometry. RESULTS: Of 38 pre-operative women, 33 attended at 8 ± 6 weeks post-operatively and 31 at 58 ± 9 weeks post-operatively. Seven patients (18%) developed BCRL. Prior to surgery the BCRL-destined patients had a higher mean k (0.0962 ± 0.034%/min) than non-BCRL patients (0.0830 ± 0.019%/min) (p = 0.10, unpaired t test). Post-operative k values were not significantly different from pre-operative, in either the ipsilateral (operated) or contralateral limb. Also, post-operative k values did not differ significantly between both upper limbs. Furthermore, there was no significant difference between pre- and post-operative axillary activity. CONCLUSION: Patients who develop BCRL have high lymph flow pre-surgery, which may predispose them to lymphatic overload and failure. Axillary lymph node surgery has no early, measurable effect on forearm muscle lymph flow despite surgical disruption of routes of lymph drainage.

Probing the environment of neurotensin whilst bound to the neurotensin receptor by solid state NMR.

A functionally active analogue of neurotensin, neurotensin(8-13), has been observed whilst bound to the agonist-binding site of the rat neurotensin receptor by nuclear magnetic resonance (NMR). Through the application of slow magic angle sample spinning and high-power proton decoupling, sufficient resolution and sensitivity were obtained in the carbon-13 spectrum to allow an assignment of many of the side chain resonances arising from uniformly carbon-13/nitrogen-15-labelled neurotensin(8-13) whilst bound to the neurotensin receptor. Significant perturbations in carbon-13 chemical shift were observed upon the binding of the neurotensin(8-13) to the receptor. Most importantly significant shifts were observed in both the carboxy terminus and tyrosine side chain of the neurotensin(8-13), suggesting that these sites are important in the interaction of the neurotensin with the agonist-binding site on the neurotensin receptor. Conversely, no perturbations were observed for the carbon-13 sites within the guanidinium groups of the arginine side chains, indicating little interaction with the receptor-binding site, or a shielding of the local environment by the surrounding nitrogen atoms. These NMR observations lend further support to previous structure-activity studies, site-directed mutagenesis and modelling studies of the agonist-binding site of the neurotensin receptor, from which the same specific residues for which NMR perturbations were observed are important for neurotensin receptor activation by neurotensin.

Restricted expression of a zinc finger protein in male germ cells.

Zfp-37 is a zinc finger protein gene expressed in male germ cells. The cDNA detected two transcripts on Northern blots of testis RNA, with expression first detected at around day 19. To establish the pattern of expression of the protein we have raised antibodies to ZFP-37 and used them on thin sections of testis and on Western blots. On Western blots the antibody detected two proteins exclusively in testis extracts, confirming the previous mRNA expression data. A time-course study revealed that the larger of the two proteins appears at about day 22 but the smaller one is not detected until day 34. Analysis of the expression of these two proteins in purified germ cell preparations revealed that the smaller protein is only detectable in the elongating spermatids or residual bodies. Data from thin sections showed that most, but not all, of the protein recognized by the antibody is in the nucleus, a result further confirmed by Western blotting. These results are discussed in the light of the possible role of this protein in regulating spermatogenesis.

Production, characterisation and use of monoclonal antibodies to human interleukin-5 in an enzyme-linked immunosorbent assay.

Two mouse monoclonal antibodies (Mabs) against recombinant human interleukin-5(rhIL-5) have been produced, characterised and purified. Both are IgG1 antibodies and neutralised the activity of rhIL-5 in the B13 assay. Neither Mab cross-reacted with mouse IL-5. A two-site sandwich enzyme-linked immunosorbent assay (ELISA) was developed with different combinations of the mouse Mabs and also a rat anti-mouse IL-5 Mab, TRFK5, which also has activity against rhIL-5. The most sensitive assay, with a lower detection limit of 0.5 ng/ml IL-5, used TRFK5 as the capture antibody and the mouse anti-human IL-5 Mab as second antibody. The sensitivity of this assay was increased by an enhanced chemiluminescent reagent and resulted in a lower limit of detection around 40 pg/ml IL-5.

Imipramine and phenelzine decrease glutamate overflow in the prefrontal cortex--a possible mechanism of neuroprotection in major depression?

Antidepressant drugs have been used for decades, but the neurobiological substrate of their efficacy is not completely understood. Although these drugs have well-established effects on monoamines, evidence is emerging that they may also affect other neurotransmitter systems. It has been shown that treatment with a wide range of antidepressants changes the binding characteristics of the N-methyl-D-aspartate type of glutamate receptor. This change is delayed and occurs only in the cortex. The mechanism that triggers it is unknown. We hypothesized that N-methyl-D-aspartate receptor alterations may be due to changes in the dynamics of cortical excitatory amino acid release. Such changes are of particular interest in areas such as the prefrontal cortex, a region involved in stress responses and affected in major depression. We investigated the effects of two antidepressants with different modes of action, imipramine and phenelzine, on glutamate and aspartate outflow in rat prefrontal cortex and striatum. We showed that antidepressants significantly decreased stimulated glutamate outflow. The effect had a rapid onset, was sustained during chronic administration and was only seen in the prefrontal cortex. This change may initiate receptor alterations. Furthermore, if antidepressants can dampen states of hyperglutamatergic activity and the subsequent excitotoxicity, their chronic use may have a considerable neuroprotective potential in major depression.