Protein Profiling of Placental Extracellular Vesicles in Gestational Diabetes Mellitus.

Throughout pregnancy, some degree of insulin resistance is necessary to divert glucose towards the developing foetus. In gestational diabetes mellitus (GDM), insulin resistance is exacerbated in combination with insulin deficiency, causing new-onset maternal hyperglycaemia. The rapid reversal of insulin resistance following delivery strongly implicates the placenta in GDM pathogenesis. In this case-control study, we investigated the proteomic cargo of human syncytiotrophoblast-derived extracellular vesicles (STBEVs), which facilitate maternal-fetal signalling during pregnancy, in a UK-based cohort comprising patients with a gestational age of 38-40 weeks. Medium/large (m/l) and small (s) STBEVs were isolated from GDM (n = 4) and normal (n = 5) placentae using ex vivo dual-lobe perfusion and subjected to mass spectrometry. Bioinformatics were used to identify differentially carried proteins and mechanistic pathways. In m/lSTBEVs, 56 proteins were differently expressed while in sSTBEVs, no proteins reached statistical difference. Differences were also observed in the proteomic cargo between m/lSTBEVs and sSTBEVs, indicating that the two subtypes of STBEVs may have divergent modes of action and downstream effects. In silico functional enrichment analysis of differentially expressed proteins in m/lSTBEVs from GDM and normal pregnancy found positive regulation of cytoskeleton organisation as the most significantly enriched biological process. This work presents the first comparison of two populations of STBEVs' protein cargos (m/l and sSTBEVs) from GDM and normal pregnancy isolated using placenta perfusion. Further investigation of differentially expressed proteins may contribute to an understanding of GDM pathogenesis and the development of novel diagnostic and therapeutic tools.

Neuropsychiatric symptoms in a patient with Cushing's syndrome.

Cushing's syndrome (CS) may present with different neurological and/or psychiatric symptoms including anxiety, depression, cognitive impairment and psychosis. Psychosis is a rare clinical manifestation, with literature limited to case reports. We report a case of a 52-year-old woman with psychosis secondary to CS who was mis-diagnosed as schizophrenia-like psychosis. This case highlights the importance of considering CS as a differential when ruling out medical causes in patients with either new or persistent mental health disturbances.

Secondary hypertension: An update on the diagnosis and localisation of a pheochromocytoma or paraganglioma.

Most cases of hypertension are because of essential hypertension, however 5% - 15% of cases can be a result of a secondary cause. In this article, we focus on the endocrine causes of secondary hypertension with a particular focus on pheochromocytomas (PCCs) and paragangliomas (PGLs). Around 15 endocrine disorders can initially present with hypertension. Amongst those PCCs and PGLs are rare but potentially life-threatening causes. An early diagnosis and timely referral can be life-saving. Herein, we present an approach for screening and diagnosis of these patients and focus on the importance of genetic testing.

SDHB-Associated Paraganglioma Syndrome in Africa-A Need for Greater Genetic Testing.

A germline mutation is identified in almost 40% of pheochromocytoma/paraganglioma (PPGL) syndromes. Genetic testing and counseling are essential for the management of index cases as well as presymptomatic identification and preemptive management of affected family members. Mutations in the genes encoding the mitochondrial enzyme succinate dehydrogenase (SDH) are well described in patients with hereditary PPGL. Among patients of African ancestry, the prevalence, phenotype, germline mutation spectrum, and penetrance of SDH mutations is poorly characterized. We describe a multifocal paraganglioma in a young African male with an underlying missense succinate dehydrogenase subunit B (SDHB) mutation and a history of 3 first-degree relatives who died at young ages from suspected cardiovascular causes. The same SDHB mutation, Class V variant c.724C>A p.(Arg242Ser), was detected in one of his asymptomatic siblings. As there are limited data describing hereditary PPGL syndromes in Africa, this report of an SDHB-associated PPGL is a notable contribution to the literature in this growing field. Due to the noteworthy clinical implications of PPGL mutations, this work highlights the existing need for broader genetic screening among African patients with PPGL despite the limited healthcare resources available in this region.

Acromegaly with empty sella syndrome.

SUMMARY: Acromegaly is a rare, chronic progressive disorder with characteristic clinical features caused by persistent hypersecretion of growth hormone (GH), mostly from a pituitary adenoma (95%). Occasionally, ectopic production of GH or growth hormone-releasing hormone (GHRH) with resultant GH hypersecretion may lead to acromegaly. Sometimes localizing the source of GH hypersecretion may prove difficult. Rarely, acromegaly has been found in patients with an empty sella (ES) secondary to prior pituitary radiation and/or surgery. However, acromegaly in patients with primary empty sella (PES) is exceeding rarely and has only been described in a few cases. We describe a 47-year-old male who presented with overt features of acromegaly (macroglossia, prognathism, increased hand and feet size). Biochemically, both the serum GH (21.6 µg/L) and insulin-like growth factor 1 (635 µg/L) were elevated. In addition, there was a paradoxical elevation of GH following a 75 g oral glucose load. Pituitary MRI demonstrated an ES. In order to exclude an ectopic source of GH hypersecretion, further biochemical tests and imaging were done, which were unremarkable. Notably, increased uptake in the sella turcica on the 68Gallium DOTATATE PET/CT confirmed the ES as the likely source of GH secretion. As no overt lesion was noted, medical treatment (octreotide acetate) was initiated with a good clinical and biochemical response. At his 3 month follow-up, he reported an improvement in symptoms (fatigue and headache), however he still complained of low libido. Due to a persistently low testosterone level at follow-up, a long-acting testosterone was initiated. His GH level normalised, and IGF-1 has significantly reduced. LEARNING POINTS: The commonest cause of acromegaly is due to GH hypersecretion from pituitary adenomas (95%). Acromegaly has rarely been found in patients with ES. It is important to exclude a past history suggestive of pituitary apoplexy. Extra-pituitary source of GH such as ectopic production of GHRH with resultant GH hypersecretion needs to be excluded. In such cases, since there is no resectable mass, medical therapy is the primary treatment option.

Hyperlipidemic myeloma, a rare form of acquired dysbetalipoproteinemia, in an HIV seropositive African female.

Dysbetalipoproteinemia (DBL) is an uncommon condition characterized by a mixed hyperlipidemia due to accumulation of remnant lipoproteins and is highly atherogenic. Typically, DBL is an autosomal recessive condition requiring an additional metabolic stress with reduced apolipoprotein E (apoE) function. However, DBL is also described in patients with multiple myeloma without the characteristic apoE2/E2 mutation seen in familial DBL. Although the underlying pathogenesis in these cases is not fully characterized, it is thought to occur due to interference with apoE function by antibodies produced from clonal plasma cells. Such cases are referred to as hyperlipidemic myeloma (HLM) and have rarely been described in the literature. To our knowledge there is no prior description of HLM in HIV positive patients in Africa. We describe a case of HLM in an African woman with underlying HIV infection who presented with phenotypic and biochemical features of DBL that responded poorly to lipid lowering therapy.

Human leukocyte antigen associations with protection against tuberculosis infection and disease in human immunodeficiency virus-1 infected individuals, despite household tuberculosis exposure and immune suppression.

BACKGROUND: To determine the association of human leukocyte antigen (HLA) alleles as correlates of risk for and protection against tuberculin skin test (TST) positivity and active TB disease amongst HIV-infected adults. METHODS: Genomic DNA was extracted from 754 HIV-infected adults whole-blood. HLA-A, -B, -C and -DRB1 loci were genotyped by next generation sequencing methods. HLA alleles were analysed by the presence/absence of TST immune conversion and active TB disease and further stratified by exposure to a household TB contact, CD4+ T-cell count and, for active TB disease, TST-positivity. RESULTS: HLA-A*29:11 and - B*45:01/07 were associated with TST-positivity, while HLA-A*24:02, -A*29:02 and -B*15:16 with TST-negativity. In participants with a household TB contact, HLA-A*66:01, -A*68:02 and -B*49:01 were associated with TST-negativity. For TB disease, HLA-B*41:01, -C*06:02, -DRB1*04:01 and -DRB1*15:01 were associated with susceptibility, while HLA-B*07:02 and -DRB1*11:01 were protective, even for CD4+ T-cell count <350 cells/mm3. For initial TST-positivity and subsequent TB disease, HLA-A*01:01 and -DRB1*11:01 conveyed protection including for those with CD4+ T-cell count <350 cells/mm3. CONCLUSION: Several HLA alleles are noted as correlates of TB infection, risk and natural protection in HIV-infected individuals. HLA associations may enable risk stratification of those with HIV infection. Protective alleles may assist in future TB vaccine development.

Novel therapies for familial hypercholesterolemia.

PURPOSE OF REVIEW: Familial hypercholesterolemia is a genetic disorder of defective clearance and subsequent increase in serum LDL cholesterol (LDL-C) with a resultant increased risk of premature atherosclerotic cardiovascular disease. Despite treatment with traditional lipid-lowering therapies (LLT), most patients with familial hypercholesterolemia are unable to achieve target LDL-C. We review current and future novel therapeutic options available for familial hypercholesterolemia. RECENT FINDINGS: The use of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are effective in lowering LDL-C in patients with familial hypercholesterolemia, with a reduction in LDL-C of 60% in heterozygous familial hypercholesterolemia (HeFH) and up to 35% in homozygous familial hypercholesterolemia (HoFH). Inclisiran, another novel agent, is a small-interfering ribonucleic acid that reduces hepatic production of PCSK9 to provide a prolonged and sustained reduction in LDL-C of nearly 50% in HeFH. However, both agents require LDL receptor (LDLR) activity. Evinacumab, a novel monoclonal antibody against angiopoetin-like 3 (ANGPTL3), reduces LDL-C by 50% independent of LDLR activity. SUMMARY: Achieving a target LDL-C in familial hypercholesterolemia can be challenging with standard LLT; however, novel therapeutic modalities show remarkable reductions in LDL-C allowing nearly all patients with HeFH and a significant proportion of patients with HoFH to achieve acceptable LDL-C levels.

LIPID AND LIPOPROTEIN LEVELS IN HIV-INFECTED ADULTS WITH SEPSIS COMPARED TO HEALTHY HIV- INFECTED CONTROLS.

BACKGROUND: In acute sepsis, reduced lipid and lipoprotein levels occur in HIV negative patients, in particular, low high-density lipoprotein cholesterol (HDL-c) levels are inversely correlated with sepsis severity and increased mortality. However, due to the limited data describing lipid and lipoprotein levels in septic HIV-infected individuals we aimed to investigate the changes in this subgroup. MATERIALS AND METHODS: A prospective cross-sectional observational study of HIV-infected patients comparing admitted HIV - infected patients with sepsis to healthy controls from the antiretroviral therapy (ART) clinic. Non fasting - lipograms, ART use, diagnosis of tuberculosis (TB), markers of infection, renal function and mortality outcome to 3 months post discharge were reviewed. RESULTS: Total cholesterol (TC), low-density lipoprotein (LDL-c) and HDL-c were all significantly lower in the sepsis group (p < 0.001). HDL-c was significantly associated with a higher white cell count (p = 0.018), higher C- reactive protein (p = 0.036) and low serum albumin (p < 0.001). In those with active TB (55%) HDL-c was reduced even further (0.55 vs. 0.72mmol/L, p = 0.013). Acute kidney injury (p = 0.560) and mortality at discharge (p = 0.097) or 3 months follow up (p = 0.953) was not associated with reduced HDL-c. CONCLUSION: Septic HIV-infected patients had significantly reduced lipid and lipoprotein levels at admission. Of note however, a low HDL-c was associated with markers of infection and reductions in HDL-c was more marked in those with active TB.

Sputum culture and drug sensitivity testing outcome among X-pert Mycobacterium tuberculosis/rifampicin-positive, rifampicin-resistant sputum: A retrospective study - Not all rifampicin resistance is multi-drug resistant.

OBJECTIVE: Rifampicin-resistant (RR) tuberculosis (TB) on X-pert Mycobacterium tuberculosis/rifampicin (MTB/Rif) is assumed to be a surrogate for multi-drug resistant (MDR) TB. Following an RR result, a second specimen was taken for confirmatory culture and drug-susceptibility testing (DST). This study compared the initial diagnostic X-pert MTB/RIF result with the confirmatory DST in a high human immunodeficiency virus (HIV) seroprevalence setting. DESIGN: Records analysing demographics, HIV serostatus, prior TB treatments, and DST results were retrospectively reviewed. RESULTS: Of 604 patients with X-pert MTB/RIF RR, 374 (61.9%) had DST and were included. The mean age was 36.9 years and 82% were HIV infected. Following DST, MDR was confirmed in 49% and Rif mono-resistant (RMR) TB in 36%. Amongst RMR TB, 84% were HIV-infected, and amongst those with CD4 < 50 versus those 50-350 cells/mm3 RMR TB was noted in 51% versus 33%, respectively (P = 0.012). Primary DR was diagnosed in 43% (61% MDR and 33% RMR). CONCLUSION: Rifampicin resistance detected on a diagnostic X-pert MTB/Rif assay did not always predict MDR. Rifampicin mono-resistance is emerging amongst those with HIV co-infection and low CD4 counts (<50 cells/mm3). Research is needed to reduce the number of drugs and treatment durations for RMR TB.

Post-primary pulmonary TB haemoptysis - When there is more than meets the eye.

Haemoptysis is concerning for both patient and healthcare provider and points to the presence of severe underlying lung disease warranting investigation. Approximately 8% of patients with pulmonary tuberculosis (PTB) infection will experience haemoptysis at some point during their life [1;2]. The aetiology of haemoptysis in the setting of PTB is diverse and may occur during active or following prior PTB infection due to pulmonary complications. We describe the case of a 33-year-old female who presented with massive haemoptysis on two separate occasions within a five-month period. Her background history included PTB 6 years prior and subsequent post-TB bronchiectasis with a destroyed left lung, and the development of apical mycetoma's. Despite numerous pre-existing aetiologies that could account for haemoptysis in this patient, on this admission, a newly identified ruptured Rasmussen's aneurysm was identified by angiography and successfully treated with arterial embolization. This report serves to highlight the multitude of reasons for haemoptysis in a patient with post PTB lung destruction and the associated diagnostic challenges that may be present. In particular, we highlight the Rasmussen's aneurysm, a rare entity, as a hidden cause of haemoptysis, where despite extensive parenchymal lung disease identified on chest radiography, specialised imaging is needed to confirm the diagnosis.

Hypoparathyroidism Causing Seizures: When Epilepsy Does Not Fit.

A 24-year-old man presented to the Chris Hani Baragwanath Academic Hospital emergency department with recurrent seizures having previously been diagnosed with epilepsy from age 14. The biochemical investigations and brain imaging were suggestive of seizures secondary to hypocalcemia, and a diagnosis of idiopathic hypoparathyroidism was confirmed. After calcium and vitamin D replacement, the patient recovered well and is seizure free, and off antiepileptic therapy. This case highlights the occurrence of brain calcinosis in idiopathic hypoparathyroidism; the occurrence of acute symptomatic seizures due to provoking factors other than epilepsy; and the importance, in the correct clinical setting, of considering alternative, and sometimes treatable, causes of seizures other than epilepsy.

Unilateral absent pulmonary artery in an adult - A diagnostic and therapeutic challenge.

Unilateral absent pulmonary artery (UAPA) is a congenital abnormality rarely diagnosed in adults. UAPA has a myriad of clinical presentations and pulmonary hypertension is present in a quarter of all cases. Isolated UAPA commonly affects the right pulmonary artery and occurs as a result of abnormal development of the sixth aortic arch segment. Due to its rarity, it remains a diagnostic and therapeutic challenge. We describe a case of UAPA in an adult presenting with severe pulmonary hypertension. We describe the appropriate diagnostic approach to a patient with pulmonary hypertension and illustrate the importance of a detailed evaluation to determine the underlying aetiology, particularly in rare causes. Furthermore, we review the clinical presentation, diagnosis and management challenges of UAPA in adults.

Acute Kidney Injury, Risk Factors, and Prognosis in Hospitalized HIV-Infected Adults in South Africa, Compared by Tenofovir Exposure.

There are limited data describing acute kidney injury (AKI) in HIV-infected adult patients in resource-limited settings where tenofovir disoproxil fumarate (TDF), which is potentially nephrotoxic, is increasingly prescribed. We describe risk factors for and prognosis of AKI in HIV-infected individuals, stratified by those receiving and those naive to TDF. A prospective case cohort study of hospitalized HIV-infected adults with AKI stratified by TDF exposure. Adults (≥18 years) were recruited: clinical and biochemical data were collected at admission; their renal recovery, discharge, or mortality was ascertained as an in-patient and, subsequently, to a scheduled 3-month follow-up. Among this predominantly female (61%), almost exclusively black African cohort of 175 patients with AKI, 93 (53%) were TDF exposed; median age was 41 years (interquartile range 35-50). Median CD4 count and viral load and creatinine at baseline were 116 cells/mm3 and 110,159 copies/ml, respectively. A greater proportion of the TDF group had severe AKI on admission (61% vs. 43%, p = .014); however, both groups had similar rates of newly diagnosed tuberculosis (TB; 52%) and nonsteroidal anti-inflammatory drug (NSAID; 32%) use. Intravenous fluid was the therapeutic mainstay; only seven were dialyzed. Discharge median serum creatinine (SCr) was higher in the TDF group (p = .032) and fewer in the TDF group recovered renal function after 3 months (p = .043). Three-month mortality was 27% in both groups, but 55% of deaths occurred in hospital. Those that died had a higher SCr and more severe AKI than survivors; TB was diagnosed in 33 (70%) of those who died. AKI was more severe and renal recovery slower in the TDF group; comorbidities, risk factors, and prognosis were similar regardless of TDF exposure. Because TB is linked to higher mortality, TB coinfection in HIV-infected patients with AKI warrants more intensive monitoring. In all those with poor renal recovery, our data suggest that a lower threshold for dialysis is needed.