Double Trouble Research Articles

Reply to: Double Trouble from POLG1 and CLCN1 Variants with Intrafamilial Phenotypic Heterogeneity.

Reply to: Double Trouble from POLG1 and CLCN1 Variants with Intrafamilial Phenotypic Heterogeneity.

Double Trouble from POLG1 and CLCN1 Variants with Intrafamilial Phenotypic Heterogeneity.

I read with interest the article by Pauly and colleagues1 about a family in which the father carried the variants c.844T>G in POLG1 and c.937G>A in CLCN1. The POLG1 variant manifested with ptosis, ophthalmoparesis, parkinsonism, and depression, and the CLCN1 variant with myotonia (myoclonic twitches and muscle cramping triggered by rapid movements or sneezing) and muscle hypertrophy.1 All of his 3 children carried his POLG1 variant and 1 the CLCN1 variant, but only 2 manifested clinically.1 The study has a number of shortcomings. Missing are the results of cerebral magnetic resonance imaging and the electroencephalogram. “Twitching” and “cramping” may not only be attributable to the CLCN1 variant but also to the POLG1 variant.2 POLG1 variants may manifest with myoclonic epilepsy, which needs to be excluded as it requires a completely different therapy. This is of relevance as the deceased daughter had Alpers-Huttenlocher disease, thus intractable epilepsy. Because “twitching” was triggerable,1 we should know if the clinical phenomenon correlated with the occurrence of myotonic discharges on needle electromyography. Because the father and his son both had myopathy of the extraocular eye muscles and POLG1 variants can also manifest with myopathy of the skeletal muscles,3 we should know if the father or his son had undergone muscle biopsy to see if features for a mitochondrial disorder (MID) were present or not. Missing are results of mitochondrial DNA (mtDNA) investigations. Because POLG1 variants may secondarily cause mtDNA depletion or multiple mtDNA deletions,4 we should know if the amount of mtDNA was reduced or if there were multiple mtDNA deletions. There is no explanation provided why the second girl did not manifest clinically from the POLG1 variant. Because MIDs frequently manifest subclinically, we should know if the girl was investigated for subclinical involvement of the brain, eyes, ears, endocrine organs, heart, intestines, or kidneys. Early detection of clinical manifestations is crucial as early treatment may improve the outcome in these patients. Assuming that the girl did not even manifest subclinically, the missing penetrance of the variant should be explained. It is conceivable that secondary damage of mtDNA was not present in this girl but only in her sister and brother. It is also not discussed why the mother of the 3 children who carried the POLG1 variant c.1399GA>A did not manifest clinically. Cardiac complications may not only derive from the CLCN1 variant but also from the POLG1 variant.5 Because cardiac involvement in MIDs strongly determines the outcome of these patients, it is crucial that they undergo regular follow-up investigations and long-term electrocardiogram recordings. If ventricular arrhythmias are recorded, implantation of an implantable cardioverter-defibrillator may strongly improve the survival and outcome of these patients. Cardiac surveillance is crucial in the light of the side effects of flecainide. It should be mentioned that, among the syndromic MIDs, POLG1 variants can also cause Leigh syndrome; mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes; myoclonic epilepsy with ragged-red fibers; myoclonic epilepsy myopathy sensory ataxia; sensory ataxic neuropathy, dysarthria, ophthalmoparesis; and chronic progressive external ophthalmoplegia syndrome. Overall, this study has a number of shortcomings that should be addressed and considered for modifying the conclusions. Genetic findings need to be related to the clinical presentation, and factors determining phenotypic variability need to be discussed. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Informed patient consent and the approval of an institutional review board was not necessary for this work. There are no conflicts of interest and no funding was received for this work. There are no disclosures to report.

Collaborative Rescue from Double Trouble: Case Review

Collaborative Rescue from Double Trouble: Case Review

Masked and white coat hypertension, the double trouble of large arteries: A systematic review and meta-analysis.

Arterial damage of large arteries, addressed as c-f PWV, is recognized as independent predictor for future cardiovascular disease. The aim of this study was to systematically investigate the association of the four hypertension phenotypes with carotid-femoral pulse wave velocity (c-f PWV), in untreated patients. PubMed and Cochrane Library were searched to identify studies comparing c-f PWV levels between normotensives, sustained hypertensives, white-coat hypertensives (WCH), and masked hypertensives (MH). Meta-analysis was performed to compare the difference c-f PWV levels between these groups. Newcastle-Ottawa quality assessment scale for cross-sectional studies was used to assess study quality. MH and WCH patients had significantly increased c-f PWV values compared to the normotensive groups (d=0.96m/s, 95% CI: 0.49-1.42; I2=85%, P<.01 for MH and d=0.85m/s, 95% CI: 0.48-1.22; I2=89%, for WCH). Moreover, the sustained hypertensive population was found to have significantly increased values of c-f PWV compared to MH (d=-0.70m/s, 95% CI: -0.87 to -0.54; I2=12%, P=.33) but not compared to WCH population (d=-0.75m/s, 95% CI: -1.52-0.02; I2 =96%,). Finally, there was no significant difference between MH and WCH population (d=0.06m/s, 95% CI: -1.04 to 1.15; I2 =96%,). MH and WCH population may have increased values of c-f PWV compared to the normotensive group. These results demonstrate that these phenotypes are not clinically innocent, in the untreated population.

Double trouble: Do symptom severity and duration interact to predicting treatment outcomes in adolescent depression?

Studies suggest that depression severity and duration interact to predict outcomes in depression treatment. To our knowledge, no study has explored this question in a sample with a placebo control, two therapies, and their combination nor with adolescents. We used data from the Treatment of Adolescent Depression Study (N = 439), in which adolescent were randomized to placebo (PBO), cognitive-behavioral therapy (CBT), antidepressants medications (MEDs), or their combination (COMB). We explore the interaction between depression severity, chronicity, and treatments (vs. placebo) in predicting outcomes. There was interaction between severity and chronicity when comparing COMB and CBT with PBO, but not MEDs. In non-chronic depression, the effects of CBT were inversely related to severity to the point that CBT appeared iatrogenic with more severe depression. In chronic depression, the effects of CBT did not vary by severity, but the relative effects of COMB grew, being smallest in milder, more dysthymic-like depression, and largest in chronic-severe depression. These findings support calls to classify depression by severity and chronicity as well efforts to risk stratify patients to different intensity of care according to these variables.

Double trouble. A cryptic first record of Berghia marinae Carmona, Pola, Gosliner, &amp; Cervera 2014 in the Mediterranean Sea

AbstractIn 2014, Berghia marinae Carmona, Pola, Gosliner &amp; Cervera, 2014 from Senegal was described along with the revision of the genus Berghia Trinchese, 1877. In this study, we establish a second record for the senegalese species B. marinae in the Mediterranean Sea, 4,000 Km away from its type location. The morphological mismatch from the original description hampered its identification, and thus, a molecular approach was needed. Multilocus phylogenetic trees were inferred from Maximum-likelihood and Bayesian analyses based on partial DNA sequences of the mitochondrial cytochrome c oxidase subunit I and 16S rRNA genes, and the nuclear gene histone-3. Species delimitation analyses were performed to support the phylogenetic results and a new morphological description is provided complementing earlier information on this barely known species.

Pure Red Cell Aplasia and Antibody-Mediated Rejection: Double Trouble in 1 Kidney Transplant Recipient Solved by Intravenous Immunoglobulin Infusion: A Case Report

Acquired pure red cell aplasia (PRCA) is characterized by severe normocytic (rarely macrocytic) and normochromic anemia, a low reticulocytes count in peripheral blood, and near absence of erythroid precursors in the bone marrow, with a normal level of erythropoietin. We describe a case of the kidney transplant recipient, diagnosed with PRCA induced with parvovirus B19 infection. Our case demonstrates that although this complication is rare, it should be considered in a differential diagnosis of anemia diagnostics in immunocompromised patients. In our case reduced immune response resulted from post-transplant immunosuppressive therapy. In our patient, apart from infection by parvovirus B19, graft dysfunction due to polyomavirus BK virus infection was also detected together with histologic and serologic features of antibody-mediated renal graft rejection. Considering the entire clinical picture, intravenous immunoglobulin therapy (IVIg) was successfully introduced.

Double Trouble: The Burden of Child-rearing and Working on Maternal Mortality

We document increased old-age mortality rates among Swedish mothers of twins compared with mothers of singletons, using administrative data on mortality for 1990–2010. We argue that twins are an unplanned shock to fertility in the cohorts of older women considered. Deaths due to lung cancer, chronic obstructive pulmonary disease, and heart attacks—all of which are associated with stress during the life course—are significantly increased. Stratifying the sample by education and pension income shows the highest increase in mortality rates among highly educated mothers and those with above-median pension income. These results are consistent with the existence of a double burden on mothers’ health resulting from simultaneously child-rearing and working.

Eisenmenger syndrome with pregnancy – Double trouble

Eisenmenger syndrome is an absolute contraindication for pregnancy. However, those patients with a diagnosis in late 2nd or 3rd trimester need to be carefully evaluated with a multidisciplinary team and strictly monitored by a critical care intensivist. We present a case of Eisenmenger syndrome diagnosed late in pregnancy, managed conservatively in intensive care unit with positive airway pressure therapy.

Severe acute respiratory syndrome coronavirus-2 and tuberculosis coinfection: Double trouble

The ongoing pandemic of novel coronavirus disease 2019 (COVID-19) has received worldwide attention by becoming a major global health threat. We encountered one case with COVID-19 and tuberculosis (TB) coinfection, which has not been frequently reported. A 76-year-old female presented with acute respiratory symptoms superimposed on chronic symptoms, suggestive to have pneumonia. Oropharyngeal throat swab sample for COVID-19 was positive as detected by real-time reverse transcriptase–polymerase chain reaction assay. GeneXpert Ultra detected Mycobacterium tuberculosis complex with rifampicin resistance indeterminate. The patient was treated with appropriate management. Clinicians should suspect coinfection with TB during the ongoing pandemic of COVID-19 as therapeutic strategies need to be determined timely to improve outcomes and prevent transmission in the community.

Double Trouble: Challenges of Cancer Care in the Philippines during the COVID-19 Pandemic

Cancer care during the COVID-19 pandemic poses many challenges. This article describes these challenges in low and middle income countries such as the Philippines. It is a given fact that delays in the treatment of patients with cancer lead to poorer prognoses.1-2 However since COVID-19 was declared a pandemic by the World Health Organization last March 11, 2020, various organizations including the American Society of Clinical Oncology (ASCO)3 and the European Society of Medical Oncology (ESMO)4 issued resources advising clinicians to postpone routine follow-up visits of patients not on active cancer treatment and advocated telemedicine in place of clinic visits to limit face to face contact and the risk of possible viral transmission. But how about cancer patients with active treatment? How do we prioritize them? A clinical guideline used in Ontario ranks patients who are being treated with aggressive tumors (eg. leukemias, lymphomas, etc), patients with life-threatening situations (eg. leukemic leukostasis or medical emergencies such as febrile neutropenia and hypercalcemia) and patients already receiving treatment as top priority to be seen at the clinic.5 For oncology clinics that continue to operate during this pandemic, the first challenge would be similar to what the other countries all over the world is facing and that is making sure safety precautions are in place to ascertain the safety of both patients and health care providers. These include controlling foot traffic to the treatment facility by limiting one entry / exit point, setting up a triage or screening system to assess all patients before they come in, strictly enforcing social distancing, wearing of the appropriate personal protective equipment (PPE), proper handwashing, and decongesting clinic schedules as much as possible among others. Another challenge for low-middle countries like the Philippines, where most of the treatment institutions are centered in the urban area of Metro Manila, is the absence of public transportation due to the national government’s declaration of an enhanced community quarantine to control the viral spread.6 Furthermore, majority of the out-patient clinics of the tertiary hospitals that specialize in cancer treatment are also closed since most of the hospital efforts including logistics and manpower are channeled towards the treatment of COVID-19 patients. Emphasis should also be given to the heath care workers who are considered the true irreplaceable assets of this battle against COVID-19. Not only are they working tirelessly in 12 to 36-hour shifts, they likewise are not able go home to their families after work because they have to be quarantined in the hospital or a nearby facility. Unfortunately, reports of healthcare workers being abused and discriminated by the community have been noted because of the stigma and the possibility of being a carrier of the virus.7 Because of this stigma, some patients were reported to have lied about their history of travel and exposure which have caused deaths among doctors.8 The logistical difficulties in ensuring the safety of the patient and the health care workers, transportation problems, and the high workload and social stigma among health care workers are the main challenges of continuing cancer care in the Philippines. The fact that cancer patients needing chemotherapy are currently being displaced from their treatment centers and have nowhere to go as an effect of the national government and the health care system’s efforts to contain and limit the damage of COVID-19 to the population calls for a united stand among oncologists to advocate for the continued treatment of these patients as long as necessary precautions are undertaken to ascertain the safety of both the health care workers and the patients. This might be the biggest battle our health care system has faced in our lifetime. Let us do everything that we can to win, remembering that there are patients who have already been fighting a different battle against cancer even before this pandemic started. Keywords: COVID-19 , cancer care , Challenges

Double trouble for viruses: a hydrogel nanocomposite catches the influenza virus while shrinking and changing color

We report a virus responsive hydrogel with a dual response. The method utilizes the optical properties of gold nanoparticles (AuNPs) and the high swelling capacity of polyol-based hydrogels to form a nanocomposite of AuNPs and polyols that produces both color changes and shrinkage in the presence of Influenza A virus particles.

Double Trouble: Visual and Phonological Impairments in English Dyslexic Readers.

Developmental dyslexia is a reading disorder characterized by problems in accurate or fluent reading. A deficiency in phonological processing is thought to underpin the reading difficulties of individuals with developmental dyslexia and a variety of explanations have been proposed including deficits in phonological awareness and verbal memory. Recent investigations have begun to suggest that developmental deficits in the acquisition of reading may also co-occur with visual processing deficits, which are particularly salient for visually complex stimuli, yet these deficits have received relatively little attention from researchers. To further explore the nature of phonological and visual processing in developmental dyslexia, we administered a series of non-reading tasks tapping both domains. Unsurprisingly, individuals with developmental dyslexia performed worse than typically developing readers in phonological tasks. More intriguingly, they also struggled with visual tasks, specifically when discriminating between novel visual patterns, and in visuo-spatial working memory, which requires greater attentional control. These findings highlight that individuals with developmental dyslexia present not only with phonological impairments but also difficulties in processing visual materials. This aspect has received limited attention in previous literature and represents an aspect of novelty of this study. The dual phonological and visual impairments suggest that developmental dyslexia is a complex disorder characterized by deficits in different cognitive mechanisms that underpin reading.

Dealing with double trouble: Combination deworming against double-drug resistant cyathostomins

An alternative control regimen for drug-resistant parasites is combination deworming, where two drugs with different modes of action are administered simultaneously to target the same parasite. Few studies have investigated this in equine cyathostomins. We previously reported that an oxibendazole (OBZ) and pyrantel pamoate (PYR) combination was not sustainable against a cyathostomin population with high levels of OBZ and PYR resistance. This study consisted of a field study and two computer simulations to evaluate the efficacy of a moxidectin-oxibendazole (MOX-OBZ) combination against the same cyathostomin population. In the field study, anthelmintic treatments occurred when ten horses exceeded 100 eggs per gram. Fecal egg counts and efficacy evaluations were performed every two weeks. The two simulations utilized weather data as well as equine and parasite population parameters from the field study. The first simulation repeated the treatment schedule used in the field study over a 40 year period. The second evaluated efficacies of combination treatments using selective therapy over 40 years. In the field study, efficacies of MOX and both combination treatments were 100%. The egg reappearance period for MOX was 16 weeks, and the two combination treatments were 12 and 18 weeks. The first (46.7%) and last (40.1%) OBZ efficacies were not significantly different from each other. In the simulation study, the combination treatment delayed MOX resistance development compared to when MOX was used as a single active. This occurred despite the low efficacy of OBZ. The second set of simulations identified combination treatments used with selective therapy to be the most effective at delaying MOX resistance. Overall, this study supports the use of combination treatment against drug-resistant cyathostomins, when one of the actives exhibits high efficacy, and demonstrates benefits of this approach despite substantially lowered efficacy of the other active ingredient.

Double trouble

Over a fifty-year period, from 1944 to 1994, Thea Astley published a number of critical writings, including essays, newspaper articles and reviews, and short reflections and meditations on her craft. Despite a renewed interest in Astley’s work, however, most critical interrogations of her oeuvre focus on her novels, and more recently her poetry. As a result, Astley’s critical writing has not been afforded the same breadth and depth of investigation as her fiction. This lacuna is troubling, since Astley’s critical works are important not only for their insight, but for what they reveal about Astley’s self-representation, and in particular the dual identity that she embodied as both a teacher and a satirist. This article argues that these dual roles emerge clearly in Astley’s essays and in fact are inextricable from many of her works. Further, the tensions between these two personae — Astley as teacher and Astley as satirist — reveal natural overlaps with her imaginative writing, and reflect her changing ideas about fiction writing, literature, and education.

Double trouble for cancer gene.

Double mutations in an oncogene enhance tumor growth

Double trouble: hemophagocytic lymphohistiocytosis in a child with Dengue fever

The epidemic of Dengue is steadily increasing in more than 100 endemic countries. During critical phase, of this disease, shock with organ dysfunction and severe bleeding, can occur. Rarely, it can be further complicated by Hemophagocytic lymphohistiocytosis (HLH), which results from aberrant activation of immune mechanism. HLH is a rare, frequently fatal if untreated condition. It challenging to diagnose because initial symptoms mimic other conditions which are more common. Dengue induced Secondary Hemophagocytic lymphohistiocytosis (HLH), may be responsible for severe form of Dengue with adverse outcomes. We describe a case of an infant, with Dengue fever whose clinical situation deteriorated after being stable during initial phases of illness due to development of Secondary Hemophagocytic lymphohistiocytosis (HLH). The child had persistent fever, anemia, hepatomegaly with deranged coagulation which directed towards diagnosis of Secondary Hemophagocytic lymphohistiocytosis (HLH). We discuss the features of our case and its management to sensitize the clinicians to consider this condition in patients with severe Dengue fever.

2237 Double Trouble: Coxsackie A and B Induced Hepatitis in an Adult

INTRODUCTION: Coxsackie virus which was first isolated in 1948 is a relatively common virus predominantly effecting children. There are 23 serotypes of Coxsackie A and 6 serotypes of the Coxsackie B viral strains. Clinical manifestations are generally mild in nature. We present a rare case of a 41yo female with Coxsackie A and B virus induced hepatitis. CASE DESCRIPTION/METHODS: 41yo F PMH DM, presented 36 weeks pregnant c/o 4 days of severe SOB and b/l LE edema. Home medications included metformin, insulin and pre-natals. No recent travel or use of herbal supplements. VS were T-98.3F, BP 130/92, HR 130, RR-22. PE showed LE edema and crackles on auscultation. Pt had severe features of preeclampsia and echo showed Global Cardiomyopathy (EF 21-25%). Labs showed Ph-7.21, CO2-33, HCO3-13, Cr-0.8, LDH-252, Alb-2.7, Bili-0.9/0.3, AST-40, ALT-23, ALP-184, WBC-11.8, Plt-172, INR-1.1, high urine protein. She was intubated for airway protection and taken for C-section. Over the next 3 days pt became febrile, hypotensive, tachycardic and worsening of her labs was noted, Cr-1.5, LDH-1528, Alb-2.1, Bili-0.9/0.5, AST-767, ALT-597, ALP-127, WBC-25.9, Plt-219, INR-1.3 before they started to improve. Pt was managed with aggressive diuresis, broad spectrum abx, and IV pressors for presumed septic/cardiogenic shock. Work up was positive for Coxsackie A and B virus. Pts bilirubin never increased beyond its current values. The rest of liver disease work up was unremarkable. Pt was discharged after stabilization and optimization of her medical condition. DISCUSSION: Coxsackie belongs to the Enterovirus genus, a member of the Picornaviridaefamily. It spreads via the fecal oral route, direct contact with bodily secretions or inhalation. Diagnosis is established with a positive viral culture or an increase in IgM titers. Coxsackie virus infection presents with nonspecific febrile illness, but may include pericarditis, myocarditis, hepatitis and encephalitis. Coxsackie A causes Hand foot and mouth disease, while Coxsackie B is the culprit of hepatitis. Hepatitis as a result of Coxsackie A strain is a very rare clinical phenomenon especially in the adult population. As seen in this case, the pts hepatitis and severe cardiomyopathy were likely secondary to Coxsackie virus. Treatment of Coxsackie virus infection is mainly supportive. Although commonly viral hepatitis is a results of Hepatitis A, B, C, D, E virus, HSV, EBV, and HIV, the possibility of Coxsackie virus induced hepatitis should always be considered.

2404 Hepatic Double Trouble—A Case of Combined Hepatocellular Carcinoma and Cholangiocarcinoma

INTRODUCTION: Combined Hepatocellular carcinoma and Cholangiocarcinoma (cHCC-CC) accounts for &lt;1% of all liver malignancies and is difficult to diagnose pre-operatively. We present a case of cHCC-CC diagnosed by imaging, tumor markers and biopsy. CASE DESCRIPTION/METHODS: A 61-year-old male with advanced cirrhosis due to hepatitis C and alcohol, was admitted for hepatic encephalopathy. His alpha-fetoprotein (AFP) was elevated at 17, 771 ng/mL. MRI abdomen revealed a 2 cm mass that showed early enhancement and rapid wash-out consistent with HCC in the right lobe and 1 lesion in the left lobe that showed hyperenhancement in post contrast images which was not consistent with HCC. CA 19-9 level was elevated at 54.3 U/mL. Biopsy of the left lobe lesion showed Cholangiocarcinoma. Metastatic work up (CT chest, MRI brain, bone scan) was negative. Patient and his family chose comfort care due to the poor functional status and need for hepatectomy. DISCUSSION: There are 3 types of cHCC-CC: In type A, HCC and CC are seen at different sites in the liver, as in ours. Type B consists of juxtaposed HCC and CC that mingle with ongoing growth and type C has both within the same tumor. Imaging shows HCC features of arterial enhancement and washout and CC features of irregular surface and late enhancement. The presence of both elevated AFP and CA 19-9 should lead to the suspicion of cHCC-CC. Hepatectomy is the only curative treatment for cHCC-CC and transplant is contraindicated. Survival after resection for cHCC-CC is worse than HCC.

P.109Congenital myopathy in patients with Kabuki and Au-Kline syndromes - Double trouble or expansion of the phenotypes?

Congenital myopathies (CM) are heterogeneous neuromuscular disorders with hypotonia and weakness, often from birth, classified on the morphological features on muscle biopsy. Cardiac muscle involvement, facial dysmorphisms and involvement of the heart and other organs is well recognized. Here we describe 5 unrelated patients with clinical and histopathological features of CM, assessed in two tertiary UK neuromuscular centers, later diagnosed with Kabuki (KS) or Au-Kline syndrome (AUS). KS and AUS are multisystem disorders, with overlapping features such as distinctive facial dysmorphisms, hypotonia, intellectual disability, growth and skeletal defects and congenital heart defects (CHD). Age of patients ranged from 2 to 13 years. Onset was at birth, with hypotonia, global developmental delay, dysmorphisms, CHD and severe feeding difficulties. On examination patients were hypotonic, but muscle strength was overall satisfactory. Three patients were hypermobile, one had hemivertebrae and one congenital hip dislocation. Microcephaly, Chiari I malformation and craniosynostosis was seen in one patient, each. Three patients had hearing loss. One patient had 3 rhabdomyolysis episodes triggered by viral infections. Respiratory chain enzyme analysis, performed in 3 patients, was normal. Analysis of genes for CM and syndromic conditions with learning disability and CHD identified pathogenic heterozygous variants in the KMT2D (3 patients with KS) or HNRNPK gene (1 patient with AUS), confirming their diagnoses (test ongoing in 5th patient). Muscle biopsies in 3 KMT2D patients showed mild non-specific changes and increased central nuclei with markedly abnormal myofibre architecture in the third case. Biopsy of the patient with variants in HNRNPK showed striking congenital fibre type disproportion. This is the first report of myopathology in KS and AUS patients and might suggest a link between the proteins disrupted in these conditions and muscle structure.