Beta-Arrestin1 Prevents Preeclampsia by Downregulation of Mechanosensitive AT1-B2 Receptor Heteromers.

Preeclampsia is the most frequent pregnancy-related complication worldwide with no cure. While a number of molecular features have emerged, the underlying causal mechanisms behind the disorder remain obscure. Here, we find that increased complex formation between angiotensin II AT1 and bradykinin B2, two G protein-coupled receptors with opposing effects on blood vessel constriction, triggers symptoms of preeclampsia in pregnant mice. Aberrant heteromerization of AT1-B2 led to exaggerated calcium signaling and high vascular smooth muscle mechanosensitivity, which could explain the onset of preeclampsia symptoms at late-stage pregnancy as mechanical forces increase with fetal mass. AT1-B2 receptor aggregation was inhibited by beta-arrestin-mediated downregulation. Importantly, symptoms of preeclampsia were prevented by transgenic ARRB1 expression or a small-molecule drug. Because AT1-B2 heteromerization was found to occur in human placental biopsies from pregnancies complicated by preeclampsia, specifically targeting AT1-B2 heteromerization and its downstream consequences represents a promising therapeutic approach.

Adjunctive glucocorticoid therapy for Pneumocystis jirovecii pneumonia in solid organ transplant recipients: A multicenter cohort, 2015-2020.

Solid organ transplant recipients (SOTRs) frequently receive adjunctive glucocorticoid therapy (AGT) for Pneumocystis jirovecii pneumonia (PJP). This multicenter cohort of SOTRs with PJP admitted to 20 transplant centers in Canada, the United States, Europe, and Australia, was examined for whether AGT was associated with a lower rate of all-cause intensive care unit (ICU) admission, 90-day death, or a composite outcome (ICU admission or death). Of 172 SOTRs with PJP (median [IQR] age: 60 (51.5-67.0) years; 58 female [33.7%]), the ICU admission and death rates were 43.4%, and 20.8%, respectively. AGT was not associated with a reduced risk of ICU admission (adjusted odds ratio [aOR] [95% CI]: 0.49 [0.21-1.12]), death (aOR [95% CI]: 0.80 [0.30-2.17]), or the composite outcome (aOR [95% CI]: 0.97 [0.71-1.31]) in the propensity score-adjusted analysis. AGT was not significantly associated with at least 1 unit of the respiratory portion of the Sequential Organ Failure Assessment score improvement by day 5 (12/37 [32.4%] vs 39/111 [35.1%]; P = .78). We did not observe significant associations between AGT and ICU admission or death in SOTRs with PJP. Our findings should prompt a reevaluation of routine AGT administration in posttransplant PJP treatment and highlight the need for interventional studies.

The 10 essential questions regarding lipoprotein(a).

PURPOSE OF REVIEW: Lp(a) is one of the most atherogenic lipoproteins, and significant progress has been made to understand its pathophysiology over the last 20 years. There are now selective therapies in late-stage clinical trials to lower Lp(a). Yet there are many outstanding questions about Lp(a). This review outlines 10 of the most burning questions and tries to answer some of them. RECENT FINDINGS: Antisense oligonucleotide (ASO) treatment is currently the most advanced therapy to lower plasma Lp(a) by 60-80%. There are, however, also two small molecule medications in early stage of development with similar efficacy. SUMMARY: This review aims to answer important preclinical and clinical questions about the metabolism and physiological role of Lp(a) and also outlines possible therapeutic approaches with nutraceuticals, currently available lipid-lowering therapies and new medications. In addition, ways are illustrated to use Lp(a) as a marker to better predict cardiovascular risk.

Noroviral diarrhea in solid organ transplant recipients: An analysis of interventions and outcomes.

INTRODUCTION: Noroviral infection can lead to chronic diarrhea in solid organ transplant (SOT) recipients with significant morbidity and mortality. Existing literature has described a wide spectrum of illness and has not come to a consensus on the optimal management of this condition. METHODS: We undertook a retrospective review of all adult SOT recipients between 1/1/2018 and 12/31/2020 who were diagnosed with their first episode of noroviral diarrhea (NVD). Demographic, clinical interventions, and outcomes within 6 months of diagnosis were recorded. Patients' outcomes were classified as either resolved, improved or persistent at 6 months. RESULTS: Seventy-nine SOT recipients were included. Thirty-eight patients (48%) had chronic diarrhea at baseline (CDB). Thirty-two patients (40%) received nitazoxanide, 28 patients (35%) had their immunosuppression adjusted and seven patients (9%) received intravenous immunoglobulin. Diarrhea improved or resolved in 68 patients (85%). Improvement or resolution of diarrhea was observed in 98% of those who did not have history of chronic diarrhea versus 74% in those who did (p = .002). NVD improved in all 12 patients who had mycophenolate discontinued, although this was not statistically significant (p = .131). CONCLUSION: CDB was associated with worse outcomes regardless of intervention. A low threshold to test for NVD in SOT recipients with chronic diarrhea is prudent to prevent delayed diagnosis.

Australian Atherosclerosis Society Position Statement on Lipoprotein(a): Clinical and Implementation Recommendations.

This position statement provides guidance to cardiologists and related specialists on the management of adult patients with elevated lipoprotein(a) [Lp(a)]. Elevated Lp(a) is an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). While circulating Lp(a) levels are largely determined by ancestry, they are also influenced by ethnicity, hormones, renal function, and acute inflammatory events, such that measurement should be done after accounting for these factors. Further, circulating Lp(a) concentrations should be estimated using an apo(a)-isoform independent assay that employs appropriate calibrators and reports the results in molar units (nmol/L). Selective screening strategies of high-risk patients are recommended, but universal screening of the population is currently not advised. Testing for elevated Lp(a) is recommended in all patients with premature ASCVD and those considered to be at intermediate-to-high risk of ASCVD. Elevated Lp(a) should be employed to assess and stratify risk and to enable a decision on initiation or intensification of preventative treatments, such as cholesterol lowering therapy. In adult patients with elevated Lp(a) at intermediate-to-high risk of ASCVD, absolute risk should be reduced by addressing all modifiable behavioural, lifestyle, psychosocial and clinical risk factors, including maximising cholesterol-lowering with statin and ezetimibe and, where appropriate, PCSK9 inhibitors. Apheresis should be considered in patients with progressive ASCVD. New ribonucleic acid (RNA)-based therapies which directly lower Lp(a) are undergoing clinical trials.

Early Clostridioides difficile infection characterizations, risks, and outcomes in allogeneic hematopoietic stem cell and solid organ transplant recipients.

BACKGROUND: Clostridioides difficile infection (CDI) frequently complicates allogeneic hematopoietic stem cell (allo-HCT) and solid organ transplantation (SOT). METHODS: We retrospectively analyzed risk factors and outcomes of CDI occurring within 30 days of transplant. RESULTS: Between March 2010 and June 2015, 466 allo-HCT and 1454 SOT were performed. The CDI cumulative incidence (95% CI) was 10% (8-13) and 4% (3-5), following allo-HCT and SOT, respectively (p < .01), occurring at a median (range) 7.5 days (1-30) and 11 (1-30), respectively (p = .18). In multivariate analysis, fluoroquinolones use within 14 days pre-transplantation was a risk factor for CDI following allo-HCT (HR 4.06 [95% CI 1.31-12.63], p = .02), and thoracic organ(s) transplantation was a risk factor for CDI following SOT (HR 3.03 [95% CI 1.31-6.98]) for lung and 3.90 (1.58-9.63) for heart and heart/kidney transplant, p = .02. Compared with no-CDI patients, the length of stay (LOS) was prolonged in both allo-HCT (35 days [19-141] vs. 29 [13-164], p < .01) and SOT with CDI (16.5 [4-101] vs. 7 [0-159], p < .01), though not directly attributed to CDI. In allo-HCT, severe acute graft-versus-host disease (aGVHD) occurred more frequently in patients with CDI (33.3% vs. 15.8% without CDI, p = .01) and most aGVHD (87.5%) followed CDI. Non-relapse mortality or overall survival, not attributed to CDI, were also similar in both allo-HCT and SOT. CONCLUSIONS: Early post-transplant CDI is frequent, associated with fluoroquinolones use in allo-HCT and the transplanted organ in SOT, and is associated with longer LOS in both the groups without difference in survival but with increased aGVHD in allo-HCT.

Clostridioides difficile infection in solid organ and hematopoietic stem cell transplant recipients: A prospective multinational study.

BACKGROUND: Clostridioides difficile infection (CDI) is a significant cause of morbidity and mortality in recipients of solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT). In retrospective single center analyses, severe disease and relapse are common. We undertook an international, prospective cohort study to estimate the response to physician determined antibiotic treatment for CDI in patients with SOT and HSCT. METHODS: Adults with a first episode of CDI within the first 2 years of SOT or HSCT were enrolled. Demographics, comorbidities, and medication history were collected, and over 90 days of follow-up clinical cure, recurrences, and complications were assessed. Logistic regression was used to study associations of baseline predictors of clinical cure and recurrence. Odds ratios (ORs) and 95% confidence intervals (CIs) are cited. RESULTS: A total of 132 patients, 81 SOT and 51 HSCT (32 allogeneic), were enrolled with a median age of 56 years; 82 (62%) were males and 128 (97%) were hospitalized at enrollment. One hundred and six (80.3%) were diagnosed by DNA assay. CDI occurred at a median of 20 days post-transplant (interquartile range, IQR: 6-133). One hundred and eight patients (81.8%) were on proton pump inhibitors; 126 patients (95.5%) received antibiotics within the 6 weeks before CDI. The most common initial CDI treatments prescribed, on or shortly before enrollment, were oral vancomycin alone (50%) and metronidazole alone (36%). Eighty-three percent (95% CI: 76, 89) of patients had clinical cure; 18% (95% CI: 12, 27) of patients had recurrent CDI; global clinical cure occurred in 65.2%. Of the 11 patients who died, two (1.5% of total) were related to CDI. In multivariable logistic regression analyses, the type of initial treatment was associated with clinical cure (p = .009) and recurrence (p = .014). A history of cytomegalovirus (CMV) after transplant was associated with increased risk of recurrence (44% with versus 13% without CMV history; OR: 5.7, 95% CI: 1.5, 21.3; p = .01). CONCLUSIONS: Among adults who develop CDI after SOT or HSCT, despite their immunosuppressed state, the percentage with clinical cure was high and the percentage with recurrence was low. Clinical cure and recurrence varied by type of initial treatment, and CMV viremia/disease was associated with an increased risk of recurrence.

An Optimization Model for Appraising Intrusion-Detection Systems for Network Security Communications: Applications, Challenges, and Solutions.

Cyber-attacks are getting increasingly complex, and as a result, the functional concerns of intrusion-detection systems (IDSs) are becoming increasingly difficult to resolve. The credibility of security services, such as privacy preservation, authenticity, and accessibility, may be jeopardized if breaches are not detected. Different organizations currently utilize a variety of tactics, strategies, and technology to protect the systems' credibility in order to combat these dangers. Safeguarding approaches include establishing rules and procedures, developing user awareness, deploying firewall and verification systems, regulating system access, and forming computer-issue management groups. The effectiveness of intrusion-detection systems is not sufficiently recognized. IDS is used in businesses to examine possibly harmful tendencies occurring in technological environments. Determining an effective IDS is a complex task for organizations that require consideration of many key criteria and their sub-aspects. To deal with these multiple and interrelated criteria and their sub-aspects, a multi-criteria decision-making (MCMD) approach was applied. These criteria and their sub-aspects can also include some ambiguity and uncertainty, and thus they were treated using q-rung orthopair fuzzy sets (q-ROFS) and q-rung orthopair fuzzy numbers (q-ROFNs). Additionally, the problem of combining expert and specialist opinions was dealt with using the q-rung orthopair fuzzy weighted geometric (q-ROFWG). Initially, the entropy method was applied to assess the priorities of the key criteria and their sub-aspects. Then, the combined compromised solution (CoCoSo) method was applied to evaluate six IDSs according to their effectiveness and reliability. Afterward, comparative and sensitivity analyses were performed to confirm the stability, reliability, and performance of the proposed approach. The findings indicate that most of the IDSs appear to be systems with high potential. According to the results, Suricata is the best IDS that relies on multi-threading performance.

Lp(a) and the Risk for Cardiovascular Disease: Focus on the Lp(a) Paradox in Diabetes Mellitus.

Lipoprotein(a) (Lp(a)) is one of the strongest causal risk factors of atherosclerotic disease. It is rich in cholesteryl ester and composed of apolipoprotein B and apo(a). Plasma Lp(a) levels are determined by apo(a) transcriptional activity driven by a direct repeat (DR) response element in the apo(a) promoter under the control of (HNF)4α Farnesoid-X receptor (FXR) ligands play a key role in the downregulation of APOA expression. In vitro studies on the catabolism of Lp(a) have revealed that Lp(a) binds to several specific lipoprotein receptors; however, their in vivo role remains elusive. There are more than 1000 publications on the role of diabetes mellitus (DM) in Lp(a) metabolism; however, the data is often inconsistent and confusing. In patients suffering from Type-I diabetes mellitus (T1DM), provided they are metabolically well-controlled, Lp(a) plasma concentrations are directly comparable to healthy individuals. In contrast, there exists a paradox in T2DM patients, as many of these patients have reduced Lp(a) levels; however, they are still at an increased cardiovascular risk. The Lp(a) lowering mechanism observed in T2DM patients is most probably caused by mutations in the mature-onset diabetes of the young (MODY) gene and possibly other polymorphisms in key transcription factors of the apolipoprotein (a) gene (APOA).

Hemophagocytic lymphohistiocytosis induced by Toxoplasma gondii infection diagnosed by a bone marrow biopsy and DNA next-generation sequencing in an allogeneic hematopoietic stem cell transplant recipient.

In the United States, toxoplasmosis following allogeneic hematopoietic stem transplant (allo-HCT) is very rare with a rate only between 0.5% and 2%. The reported rates of hemophagocytic lymphohistiocytosis (HLH) following allo-HCT range between 0.3% and 17%. Secondary HLH due to toxoplasmosis infection is extremely rare. Herein, we report a case of secondary HLH due to toxoplasmosis following allo-HCT. The diagnosis was reached by a bone marrow biopsy and confirmed by DNA next generation sequencing and immunohistochemical (IHC) staining. The IHC staining included CD1a, a stain previously known to react with cells infected by Leishmania, here we show CD1a staining of macrophages infected with Toxoplasma gondii. Our report highlights the utility of bone marrow biopsy in diagnosing parasitic infection underlying HLH in post-transplant settings. The pre-transplant evaluation of patients from low endemic countries, is a great opportunity to obtain a travel history to determine the risks and the preventative measures against opportunistic infections including toxoplasmosis.

Essentials of a new clinical practice guidance on familial hypercholesterolaemia for physicians.

Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease. New clinical practice recommendations are presented to assist practitioners in enhancing the care of all patients with FH. Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors and appropriate use of low-density lipoprotein (LDL)-cholesterol-lowering therapies including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The recommendations need to be utilised using judicious clinical judgement and shared decision-making with patients and families. New government-funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of the recommendations. However, a comprehensive implementation science and practice strategy is required to ensure that the guidance translates into benefit for all families with FH.

Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in Australia.

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all Australian families with or at risk of FH.

Gaps in the Care of Familial Hypercholesterolaemia in Australia: First Report From the National Registry.

BACKGROUND: Familial hypercholesterolaemia (FH) is under-diagnosed and under-treated worldwide, including Australia. National registries play a key role in identifying patients with FH, understanding gaps in care and advancing the science of FH to improve care for these patients. METHODS: The FH Australasia Network has established a national web-based registry to raise awareness of the condition, facilitate service planning and inform best practice and care services in Australia. We conducted a cross-sectional analysis of 1,528 FH adults enrolled in the registry from 28 lipid clinics. RESULTS: The mean age at enrolment was 53.4±15.1 years, 50.5% were male and 54.3% had undergone FH genetic testing, of which 61.8% had a pathogenic FH-causing gene variant. Only 14.0% of the cohort were family members identified through cascade testing. Coronary artery disease (CAD) was reported in 28.0% of patients (age of onset 49.0±10.5 years) and 64.9% had at least one modifiable cardiovascular risk factor. The mean untreated LDL-cholesterol was 7.4±2.5 mmol/L. 80.8% of patients were on lipid-lowering therapy with a mean treated LDL-cholesterol of 3.3±1.7 mmol/L. Among patients receiving lipid-lowering therapies, 25.6% achieved an LDL-cholesterol target of <2.5 mmol/L without CAD or <1.8 mmol/L with CAD. CONCLUSION: Patients in the national FH registry are detected later in life, have a high burden of CAD and risk factors, and do not achieve guideline-recommended LDL-cholesterol targets. Genetic and cascade testing are under-utilised. These deficiencies in care need to be addressed as a public health priority.

Familial Hypercholesterolaemia in 2020: A Leading Tier 1 Genomic Application.

Familial hypercholesterolaemia (FH) is caused by a major genetic defect in the low-density lipoprotein (LDL) clearance pathway. Characterised by LDL-cholesterol elevation from birth, FH confers a significant risk for premature coronary artery disease (CAD) if overlooked and untreated. With risk exposure beginning at birth, early detection and intervention is crucial for the prevention of CAD. Lowering LDL-cholesterol with lifestyle and statin therapy can reduce the risk of CAD. However, most individuals with FH will not reach guideline recommended LDL-cholesterol targets. FH has an estimated prevalence of approximately 1:250 in the community. Multiple strategies are required for screening, diagnosing and treating FH. Recent publications on FH provide new data for developing models of care, including new therapies. This review provides an overview of FH and outlines some recent advances in the care of FH for the prevention of CAD in affected families. The future care of FH in Australia should be developed within the context of the National Health Genomics Policy Framework.

Long-Term Infectious and Noninfectious Outcomes of Monthly Alemtuzumab as a Calcineurin Inhibitor- and Steroid-Free Regimen for Pancreas Transplant Recipients.

Multiple doses of alemtuzumab for immunosuppressive therapy of patients with hematologic malignancies and hematopoietic stem cell transplant have been associated with a high rate of infection. In transplantation, limited alemtuzumab dosing has been successfully used as induction immunosuppression. The effect of multiple doses of alemtuzumab, used as maintenance therapy to minimize steroid and/or calcineurin inhibitor toxicity in solid organ transplant recipients, is unknown. We evaluated the infectious and noninfectious outcomes of 179 pancreas transplant recipients treated with alemtuzumab for induction and maintenance therapy (extended alemtuzumab exposure (EAE)) from 2/28/2003 through 8/31/2005, compared with 159 pancreas transplant recipients with standard induction and maintenance (SIM) therapy performed before (1/1/2002 until 12/31/2002) and after (1/1/2006 until 12/31/2006) the implementation of EAE. EAE was associated with higher risk of overall infections (hazard ratio (HR) 1.33 (1.06-1.66), P=0.01), bacterial infections (HR 1.33 (1.05-1.67), P=0.02), fungal infections (HR 1.86 (1.28-2.71), P < 0.01), and cytomegalovirus infections (HR 2.29 (1.39-3.77), P < 0.01). In addition, EAE was associated with higher risk of acute cellular rejection (HR 2.09 (1.46-2.99), P < 0.01). In conclusion, while a limited alemtuzumab dosing is safe and effective for induction therapy in pancreas transplantation, EAE combined with steroid and calcineurin minimization is associated with a high risk of infectious complications and acute cellular rejection.

Status of PCSK9 Monoclonal Antibodies in Australia.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAb) have progressed from showing marked low density lipoprotein cholesterol lowering in early phase trials through to reducing cardiovascular events in large clinical outcome trials. Recently in Australia, the indication for evolocumab has been expanded to include both heterozygous and homozygous familial hypercholesterolaemia under the Pharmaceutical Benefits Scheme (PBS). With prices remaining high currently their use in non-familial hypercholesterolaemia in Australia remains by private prescription only at this stage. This manuscript summarises the major outcomes trials of the PCSK9 mAbs and the secondary analyses that have assessed their benefits in high risk patient groups, and describes the consensus of authors on which patients would most likely benefit from PCSK9 mAb therapy.

Lipoprotein (a): a historical appraisal.

Initially, lipoprotein (a) [Lp(a)] was believed to be a genetic variant of lipoprotein (Lp)-B. Because its lipid moiety is almost identical to LDL, Lp(a) has been deliberately considered to be highly atherogenic. Lp(a) was detected in 1963 by Kare Berg, and individuals who were positive for this factor were called Lpa+ Lpa+ individuals were found more frequently in patients with coronary heart disease than in controls. After the introduction of quantitative methods for monitoring of Lp(a), it became apparent that Lp(a), in fact, is present in all individuals, yet to a greatly variable extent. The genetics of Lp(a) had been a mystery for a long time until Gerd Utermann discovered that apo(a) is expressed by a variety of alleles, giving rise to a unique size heterogeneity. This size heterogeneity, as well as countless mutations, is responsible for the great variability in plasma Lp(a) concentrations. Initially, we proposed to evaluate the risk of myocardial infarction at a cut-off for Lp(a) of 30-50 mg/dl, a value that still is adopted in numerous epidemiological studies. Due to new therapies that lower Lp(a) levels, there is renewed interest and still rising research activity in Lp(a). Despite all these activities, numerous gaps exist in our knowledge, especially as far as the function and metabolism of this fascinating Lp are concerned.

The immune microenvironment in cutaneous leishmaniasis.

BACKGROUND: Cutaneous leishmaniasis is an infection that has spread to non-endemic regions, stimulating recent interest for the enhanced understanding of this disease. Downregulation of the CD1a receptor on Langerhans cells has been described in various cutaneous infections. OBJECTIVE: In this study, the immune response across different Ridley patterns and parasitic indices is outlined in a case series of cutaneous leishmaniasis. METHODS: Skin punch biopsies from the interface of normal and lesional cutaneous leishmaniasis were collected from 33 patients with molecularly confirmed Leishmania tropica or L. major infection. Ridley patterns (2-5) were assessed for various clinicopathological features including age, gender, disease duration, parasitic index and constituents of the inflammatory infiltrate. CD1a, CD68, CD3, CD4, CD8, CD20 and CD138 stains were performed on normal skin tissue, cutaneous leishmaniasis biopsies and cytospin/cell block cytology preparations of cultured leishmania promastigotes. CD1a was quantified per mm2 in the epidermis and dermis. The remaining stains were graded according to a 4-tiered grading system [0 (0-4%); 1 (5-24%); 2 (25-49%); 3 (50-74%) and 4 (75-100%). RESULTS: Total CD1a expression significantly decreased (14-fold) from parasitic indices (0-2) to (5-6); (ρ < 0.001). CD1a expression in the epidermis was at least 5-fold lower than normal skin (58 vs. 400 cells/mm2), inversely correlating with the parasitic index. There was an increase in dermal CD1a Langerhans cells (33 vs. 0 cells/mm² in the dermis). CD1a and CD68 staining of amastigotes was strong and diffuse, whereas promastigotes were negative. The major inflammatory infiltrate, in all Ridley patterns, consisted of macrophages and double-negative CD3(+) CD4(-) CD8(-) T lymphocytes. The double-negative CD3 T cells formed a ring around the parasitic laden macrophages. Apart from CD1a, there was no significant difference in inflammatory markers between the various Ridley patterns and parasitic indices. Disease duration did not correlate with Ridley pattern. CONCLUSION: The significant decrease in CD1a expression is postulated by two mechanisms; either via direct CD1a receptor uptake by leishmania amastigotes and/or negative feedback inhibition of CD1a Langerhans cells by double-negative CD3 T-regulatory cells. Modulation of the immune microenvironment in cutaneous leishmaniasis represents a potential therapeutic and prophylactic target.

Pulmonary computed tomography scan findings in chronic granulomatous disease.

BACKGROUND: Chronic granulomatous disease is a phagocyte defect, characterised by recurrent infections in different organs due to a defect in NADPH oxidase complex. This study was performed to investigate pulmonary problems of CGD in a group of patients who underwent computed tomography (CT) scan. METHODS: Computed tomography scan was performed in 24 patients with CGD. The findings of the CT scan were documented in all of these patients. RESULTS: Areas of consolidation and scan formation were the most common findings, which were detected in 79% of the patients. Other abnormalities in order of frequencies were as follows: small pulmonary nodules (58%); mediastinal lymphadenopathy (38%); pleural thickening (25%); unilateral hilar lymphadenopathy (25%); axillary lymphadenopathy (21%); bronchiectasis (17%); abscess formation (17%); pulmonary large nodules or masses (8%); and free pleural effusion (8%). CONCLUSION: The pulmonary CT scans of the patients with CGD demonstrated a variety of respiratory abnormalities in the majority of the patients. While recurrent respiratory infections and abscesses are considered as prominent features of CGD, early diagnosis and precise check-up of the respiratory systems are needed to prevent further pulmonary complications.

When should we measure lipoprotein (a)?

Recently published epidemiological and genetic studies strongly suggest a causal relationship of elevated concentrations of lipoprotein (a) [Lp(a)] with cardiovascular disease (CVD), independent of low-density lipoproteins (LDLs), reduced high density lipoproteins (HDL), and other traditional CVD risk factors. The atherogenicity of Lp(a) at a molecular and cellular level is caused by interference with the fibrinolytic system, the affinity to secretory phospholipase A2, the interaction with extracellular matrix glycoproteins, and the binding to scavenger receptors on macrophages. Lipoprotein (a) plasma concentrations correlate significantly with the synthetic rate of apo(a) and recent studies demonstrate that apo(a) expression is inhibited by ligands for farnesoid X receptor. Numerous gaps in our knowledge on Lp(a) function, biosynthesis, and the site of catabolism still exist. Nevertheless, new classes of therapeutic agents that have a significant Lp(a)-lowering effect such as apoB antisense oligonucleotides, microsomal triglyceride transfer protein inhibitors, cholesterol ester transfer protein inhibitors, and PCSK-9 inhibitors are currently in trials. Consensus reports of scientific societies are still prudent in recommending the measurement of Lp(a) routinely for assessing CVD risk. This is mainly caused by the lack of definite intervention studies demonstrating that lowering Lp(a) reduces hard CVD endpoints, a lack of effective medications for lowering Lp(a), the highly variable Lp(a) concentrations among different ethnic groups and the challenges associated with Lp(a) measurement. Here, we present our view on when to measure Lp(a) and how to deal with elevated Lp(a) levels in moderate and high-risk individuals.