Juvenile dermatomyositis associated with autoantibodies to small ubiquitin-like modifier activating enzyme: a report of 4 cases from North India and a review of literature

Immunologic Research - Juvenile dermatomyositis (JDM) is the commonest inflammatory myositis in children. The clinical phenotype is often characterized by the presence of myositis-specific...     

PMP22 Gene–Associated Neuropathies: Phenotypic Spectrum in a Cohort from India

Journal of Molecular Neuroscience - Reports of spectrum of clinical manifestations in PMP22 gene–associated neuropathies (duplication/mutations) are scarce. To identify the frequency of PMP22...     

Serum placental growth factor as a predictor of early onset preeclampsia in overweight/obese pregnant women

The purpose of this study was to analyze whether maternal serum placental growth factor (PlGF) could predict early onset preeclampsia (<32 weeks of gestation) in overweight/obese pregnant women, and whether it could do it more effectively than in normal/underweight pregnant women. A prospective cohort study was conducted on 1678 pregnant women with singleton pregnancies, who were grouped as underweight, normal, overweight, and obese on the basis of body mass index, followed by serum PlGF estimation at 20 to 22 weeks of gestation. A cut-off value of <144 pg/mL for PlGF was determined by Receiver Operating Characteristic curve analysis to identify risk of early onset preeclampsia. Univariate logistic regression analysis revealed significantly stronger association between PlGF <144 pg/mL and early onset preeclampsia in overweight/obese pregnant women (odds ratio 7.64; 95% confidence interval 5.34–10.12; P = .000) than in normal/underweight pregnant women (odds ratio 2.95; 95% confidence interval 1.74–4.26; P = .007). Weight and PlGF levels in study women had a significant negative correlation (r = 0.663; P = .002). Serum PlGF in early second trimester could be an effective predictor of early onset preeclampsia in overweight/obese pregnant women and may be more effective than in normal/underweight pregnant women.     

Reversibility of Retinal Microvascular Changes in Severe Falciparum Malaria

Malarial retinopathy allows detailed study of central nervous system vascular pathology in living patients with severe malaria. An adult with cerebral malaria is described who had prominent retinal whitening with corresponding retinal microvascular obstruction, vessel dilatation, increased vascular tortuosity, and blood retinal barrier leakage with decreased visual acuity, all of which resolved on recovery. Additional study of these features and their potential role in elucidating the pathogenesis of cerebral malaria is warranted.The pathogenesis of coma in falciparum malaria and its rapid reversibility are potential targets for adjunctive therapies, but they are not well-understood. Microvascular obstruction is probably an important contributor. The brain microvasculature is relatively inaccessible; it can be studied in detail only at post-mortem. Similarly, microvascular obstruction in the retina is thought to be a major contributor to the unique retinopathy of severe falciparum malaria, and, because it is easily visualized in living subjects, in-depth study is providing new and valuable insights. We describe an adult patient with cerebral malaria who had prominent retinal changes with some previously unrecognized features that resolved on recovery.A 24-year-old male truck driver from Orissa, India was admitted with severe Plasmodium falciparum malaria (parasitemia = 0.3%) with coma, generalized convulsions, hyperlactatemia, renal failure, and black urine. He had no prior medical history. Retinal photography showed bilateral patchy macular whitening with corresponding capillary non-perfusion and leakage of fluorescein caused by blood retinal barrier breakdown on fluorescein angiography (Figure 1). He was treated with intravenous artesunate, and from recovery of consciousness on day 3 to discharge, his visual acuity was markedly reduced (counting digits only), with loss of red–green color vision. Repeat examination on day 55 showed that the retinal changes, angiogram abnormalities, and visual deficits had resolved (acuity 6/9 bilaterally and normal color vision). Blood vessel tortuosity measured in three arteries and three veins by a single blinded observer tracing the center line of vessels between branch points in matched pairs of retinal photographs using Adobe Photoshop CS4 (Adobe Systems, San Jose, CA)¹ was greater on day 0 than day 55 (mean ratios of vessel widths measured at 10 points in each vessel; 1.226 in arteries and 1.172 in veins; vessel lengths were 1.043 and 1.035). These differences are similar to those found previously in diabetic macular edema.¹Open in a separate windowFigure 1.(A and B) Retinal photographs and (C and D, arterial phase; E and F, late phase) fluorescein angiograms of the left eye. On day 3, increased vessel thickness and tortuosity plus (A) patchy macular whitening with corresponding areas of (C) reduced perfusion and (E) fluorescein leakage were seen. On day 55, normal vessels, (B) no whitening, and (D) normal perfusion around the fovea with (F) no leakage of fluorescein were seen.Malarial retinal whitening is thought to be caused by hypoxic opacification of the retina after obstruction of small blood vessels by sequestered parasites.^2,3 It is similar to patchy ischemic retinal whitening (PIRW), a transient early sign of central retinal vein occlusion (CRVO)² thought to represent intracellular edema of overlying retinal intermediary neurones.⁴ The degree of retinal whitening in adults and children correlates with severity of malaria and peripheral blood lactate.^5,6 Hyperlactatemia is common in severe malaria and at least partly caused by obstruction of the systemic microcirculation by sequestered parasites. Cerebrospinal fluid lactate concentrations are also raised in cerebral malaria, and in those cases it is predictive of mortality.⁷The appearance and distribution of retinal whitening are unique to severe falciparum malaria. Typically, there are multiple small lesions most prominent in the macula, particularly temporal to the fovea. This area is a watershed between the superior and inferior retinal vascular arcades and particularly vulnerable to ischemic insults. Midperipheral involvement in malaria distinguishes it from PIRW, Purtscher''s retinopathy, and cotton wool spots (sometimes also seen in malaria), which are distributed particularly around the optic disk and typically more opaque. Malarial retinopathy is considered reversible,^8,9 but this case is the first published photographic evidence of reversibility.The angiogram in this patient showed that the whitening corresponds closely to capillary non-perfusion. This finding has not been described previously in adults but is common in Malawian children with cerebral malaria.¹⁰ Post-mortem studies in Malawi have found retinal blood vessels in cerebral malaria to be packed with sequestered parasites,¹¹ similar to findings in the brain in adults.¹² Because retinal whitening⁹ and central nervous system (CNS) sequestration^13,14 are particularly prominent in patients with malarial coma (cerebral malaria), this finding suggests that small blood vessel CNS ischemia plays a major role in pathogenesis. In survivors, malarial coma is rapidly reversible and, as seen in the retina in this case, reversal of blood vessel obstruction is a plausible contributor.This patient had mildly increased tortuosity of retinal blood vessels that decreased on recovery. Although increased vascular tortuosity has not been well-described in malaria, it is a recognized feature of other vascular occlusive diseases of the retina. Vessel tortuosity is caused by a combination of vessel dilation from radial stretching and the vessel taking a more serpentine path because of longitudinal stretching.¹⁵ Several pathogenic mechanisms have been proposed for increased retinal vascular tortuosity. They include (1) increased blood flow in anemia, (2) early angiogenesis caused by ischemia or inflammation and (3) dysregulation of vascular tone caused by microvascular obstruction and relative hypoxia in diabetic retinopathy, and (4) venous congestion causing elevated vascular pressure and dilatation of blocked vessels in CRVO and raised intracranial pressure resulting in central retinal vein compression. In malaria, anemia is common, uninfected red blood cells have reduced deformability, and sequestered parasites cause microvascular and venular obstruction. Angiogenesis is probably unimportant over the short timescale.¹Increased vascular tortuosity has not been well-described previously in severe falciparum malaria, possibly because the normal appearance of retinal vessels varies significantly between individuals and subtle changes are difficult to identify. Ophthalmoscopy revealed engorgement and tortuosity of retinal veins in 26% of children with cerebral malaria in Ghana, which mostly resolved by 1 week.⁸ In our patient, comparison of retinal photographs provided a more objective measure. Means of quantifying vessel tortuosity using computer-aided image processing are under development.The angiogram in this patient showed focal leakage of fluorescein across the blood–retinal barrier (BRB) in areas of non-perfusion, suggesting a common etiology. The BRB is analogous to the blood–brain barrier, which is also mildly disrupted in cerebral malaria. Leakage from larger retinal vessels crossing ischemic areas is a well-known phenomenon in retinal ischemia. The significance of this finding as a contributor to the pathogenesis of malarial coma is not known. More angiographic studies are needed.This patient had decreased visual acuity, which had resolved at follow-up. Although it is not possible to give a cause, it is the first report of an association between macular retinal whitening and decreased visual acuity with subsequent recovery.Additional studies of malarial retinopathy have great potential to enhance our understanding of vascular changes in severe malaria. To maximize their impact, studies should use retinal photography, where possible, to allow detailed examination of the full range of fundus signs by multiple blinded observers. This examination should be done both acutely and at follow-up. Fluorescein angiography provides a highly detailed map of CNS retinal perfusion. There is a need for additional detailed studies to include assessment of vascular tortuosity to investigate its role as a potential early and sensitive marker in studies of severe malaria.The rate of reversibility of malarial retinopathy has potential as an end point in intervention studies of severe malaria, particularly for adjunctive therapies that directly target the pathogenesis. Additional information on the speed of reversibility of the various components of malarial retinopathy is needed, and studies are underway to investigate this.     

Nanostructural control of the release of macromolecules from silica sol–gels

The therapeutic use of biological molecules such as growth factors and monoclonal antibodies is challenging in view of their limited half-life in vivo. This has elicited the interest in delivery materials that can protect these molecules until released over extended periods of time. Although previous studies have shown controlled release of biologically functional BMP-2 and TGF-β from silica sol–gels, more versatile release conditions are desirable. This study focuses on the relationship between room temperature processed silica sol–gel synthesis conditions and the nanopore size and size distribution of the sol–gels. Furthermore, the effect on release of large molecules with a size up to 70 kDa is determined. Dextran, a hydrophilic polysaccharide, was selected as a large model molecule at molecular sizes of 10, 40 and 70 kDa, as it enabled us to determine a size effect uniquely without possible confounding chemical effects arising from the various molecules used. Previously, acid catalysis was performed at a pH value of 1.8 below the isoelectric point of silica. Herein the silica synthesis was pursued using acid catalysis at either pH 1.8 or 3.05 first, followed by catalysis at higher values by adding base. This results in a mesoporous structure with an abundance of pores around 3.5 nm. The data show that all molecular sizes can be released in a controlled manner. The data also reveal a unique in vivo approach to enable release of large biological molecules: the use more labile sol–gel structures by acid catalyzing above the pH value of the isoelectric point of silica; upon immersion in a physiological fluid the pores expand to reach an average size of 3.5 nm, thereby facilitating molecular out-diffusion.     

Clinical,hematological, and imaging observations in a 25-year-old woman with abetalipoproteinemia

Abetalipoproteinemia is an uncommon cause of ataxia and retinitis pigmentosa (RP). Most of the neurological and ocular manifestations occur secondary to deficiency syndromes that is consequent to fat malabsorption from the small intestine. In this report, we have described the phenotype of a young adult female who manifested with recurrent diarrheal illness in her first decade, followed by anemia, RP, and neurological involvement with progressive deafness, cerebellar and sensory ataxia, and subclinical neuropathy in her second decade of life. While RP and sensory ataxia due to vitamin E deficiency are well-recognized features of abetalipoproteinemia, deafness is rarely described. In addition, we have highlighted the abnormal posterior column signal changes in the cervical cord in this patient. Early recognition avoids unnecessary investigations and has a potential to retard the disease progression by replacing some of the deficient vitamins.     

Sarcopenia after induction therapy is associated with reduced survival in patients undergoing esophagectomy for locally-advanced esophageal cancer

BackgroundThe impact of sarcopenia on the outcome of esophageal cancer patients remains unknown in North American populations. The current study aims to investigate if sarcopenia at the time of esophagectomy for locally-advanced esophageal cancer (LAEC) is associated with survival.MethodsPatients who underwent induction therapy followed by esophagectomy for LAEC between 2010–2018 at a single institution were identified. Exclusion criteria included follow-up less than 90 days and distant metastatic disease at the time of surgery. Demographic, treatment, and outcome data were retrospectively collected. Computed tomography (CT) scans following induction therapy were analyzed to calculate skeletal muscle index (SMI). Overall survival (OS) and disease-free survival (DFS) were examined using Kaplan-Meier and Cox Proportional Hazard regression analysis.ResultsOverall, 52 patients met inclusion criteria with a median BMI of 25 (IQR, 22.4–29.1) kg/m² and age of 65 (IQR, 57–70) years. Sarcopenia was present in 75% (39/52) of patients at the time of surgery. Sarcopenic patients had a lower median BMI and higher median age when compared to non-sarcopenic patients. There was no difference in gender, race, stage, operative technique, post-operative complications, or hospital length of stay between sarcopenic and non-sarcopenic patients. With a median follow-up of 24.9 months, patients with sarcopenia at the time of esophagectomy had worse OS [median 24.3 (IQR, 9.9–34.5) vs. 50.9 (IQR, 25.6–50.9) months, P=0.0292] and DFS [median 11.7 (IQR, 6.4–25.8) vs. 29.4 (IQR, 12.8–26.7) months, P=0.0387] compared to non-sarcopenic patients.ConclusionsSarcopenia is associated with reduced overall and DFS in patients undergoing esophagectomy for LAEC.     

Obstructive Thebesian valve: anatomical study and implications for invasive cardiologic procedures

Thebesian valve is the embryological remnant of the right sinoatrial valve, guarding the coronary sinus (CS) ostium. Advanced invasive and interventional cardiac diagnostic and management tools involve cannulation of the CS ostium. The presence of obstructive Thebesian valves has been reported to lead to unsuccessful cannulation of the CS. We studied the morphology of the Thebesian valve and CS ostium to assess the possible impact of these structures on invasive cardiological procedures. One hundred fifty randomly selected human cadaveric heart specimens fixed in 10 % formalin were dissected in the customary routine manner. The Thebesian valves were classified according to their shape as semilunar/fenestrated/biconcave band like and according to their composition as membranous/fibromuscular/fibrous/muscular, and the extent to which the valve covered the CS ostium was also noted. An obstructive Thebesian valve that could interfere with the cannulation of the CS was defined as non-fenestrated (semilunar/biconcave band like) and non-membranous (fibromuscular/fibrous/muscular) valves covering >75 % of the CS ostium. Thebesian valves were present in 118 (79 %) heart specimens, of which 27 (18 %) met the criteria of being obstructive. Semilunar was the most common type of Thebesian valve in terms of shape and was observed in 65 (65/118; 55 %) hearts. This type was associated with the least mean craniocaudal (7.9 ± 0.6 mm) and mean transverse (6.25 ± 0.6 mm) diameters of the CS ostium. The mean craniocaudal diameter of the CS ostium (9.4 ± 2.1 mm) was significantly larger (p = 0.004) than the mean transverse diameter (7.15 ± 1.5 mm) in specimens with Thebesian valves, and the cranial margin of the CS ostium was free from any attachment of the Thebesian valve in all the types observed (in terms of shape). Hence, attempts to direct the tip of the catheter toward the cranial margin of the CS ostium under direct vision may lead to successful cannulation of the same when conventional techniques have been unsuccessful because of the presence of an obstructive Thebesian valve.