Early Pointers Research Articles

ECEL1 related distal arthrogryposis 5D in an Indian cohort-Report of recognizable musculoskeletal phenotype and a possible founder variant.

Distal arthrogryposis type 5D (DA5D) is clinically characterized by knee extension contractures, distal joint contractures, clubfoot, micrognathia, ptosis, and scoliosis. We report nine affected individuals from eight unrelated Indian families with DA5D. Although the overall musculoskeletal phenotype is not very distinct from other distal arthrogryposis, the presence of fixed knee extension contractures with or without scoliosis could be an important early pointer to DA5D. We also report a possible founder variant in ECEL1 along with four novel variants and further expand the genotypic spectrum of DA5D.

A Technical Glitch or Whispers of Changing Epidemiology of HPV Negative Carcinoma Cervix? An Exploratory Study

<h3>Purpose/Objective(s)</h3> To study the prevalence of HPV negative Carcinoma Cervix (CC) and its prognostic impact on survival. <h3>Materials/Methods</h3> Data of all CC who were treated with concurrent chemoradiotherapy followed by brachytherapy from 1^st Jan 2014 to 31^st December 2018 was retrieved. A total of 79 patients whose biopsy samples were available for genotyping were included in the study. DNA was extracted from cervical cell suspensions using Qiagen DSP virus kit (Ref-60704). The genotyping was done using 3B Black Bio TRUPCR HPV HR with 16/18 genotyping kit which is based on amplification of E6/E7 region by primers and probes specific for detection of 14 HPV subtypes. All procedures were followed as per instructions on the kit insert. Survival analysis was done using Kaplan Meier survival curves with log rank test used to compare the factors with respect to Overall survival (OS) and recurrence free survival (RFS). Statistical software was used for all statistical analyses. <h3>Results</h3> Seventy one percent (56/79) of the patients were HPV positive whereas 29% (23/76) were HPV negative. Out of the HPV positive patients, P16 positivity was the most predominant genotype with 73.2% (41/56) patients testing positive for it followed by P18 (14.3%). The remaining 12.5% of patients tested positive for HPV 31,35,51,52,56,58,59 and 68 subtypes. The unusual high rates of HPV negativity could be due to cervical cancers evolving independent of high-risk HPV, loss of expression of HPV, misclassification of cancers and inherent false negativity rates of the methods used for testing of HPV. All these factors were kept to a minimum by ensuring that the low and intermediate risk subtypes of HPV responsible were also tested for, the misclassification of uterine endometrioid adenocarcinoma or metastasis as CC was minimized by independent review of two experienced pathologists and testing related errors were kept at bare minimum by following the standard procedures provided by the manufacturers. Based on the extant literature, the combined false negativity rate of all the above factors, combined together, was approximately 7-8%, leaving an unexplained 21-22% of the HPV negative prevalence in the cohort. This could well be due to the rising trend of HPV negative carcinoma cervix which need a nuanced look on a broader basis as it might lead to a readjustment of our tactics in prevention and management of CC. The estimated 5-year OS of the HPV positive and HPV negative population within the study group was 84.5% and 82.6% respectively (P value=0.425). Median overall survival was not reached and needs a longer follow-up. <h3>Conclusion</h3> The HPV negativity rates among patients of CC in our study cohort were unusually high (29%). Detailed and systematic perusal of possible factors contributing to such high rates still left an uncharted void of approximately 21% which might be an early pointer towards rising trend of HPV negative CC.

Moderating Effects of Early Pointing on Developmental Trajectories of Word Comprehension and Production.

The present study investigated the moderating role of early communicative pointing on the developmental trends of word comprehension and production over the second year of life. Seventy-seven infants were involved in an experimental pointing task (T-POINT) in sessions at 9 and 12 months, and the MB-CDI questionnaire was filled in by their parents at 15, 18 and 24 months. Based on the age at which the infants were seen to use pointing, they were classified into three groups: the ‘Early’ pointers, who first pointed during the 9-month session; the ‘Typical’ pointers, who first pointed in the 12-month session; and the ‘Late’ pointers, who never pointed in either of the sessions. Using multilevel modelling, we traced the developmental trajectories and individual differences for the two lexical domains of word comprehension and production according to the three pointing groups. The main results showed that compared to the Typical pointers: (i) the Early pointers were faster for word comprehension development, and were similar for word production; (ii) the Late pointers showed lexical delay before 18 months for word comprehension, and between 18 and 24 months for word production. These data are discussed in light of the different roles of early pointing on receptive compared to expressive vocabulary development.

Autoimmunity in Wiskott-Aldrich Syndrome: Updated Perspectives.

Wiskott–Aldrich syndrome (WAS) is an uncommon X-linked combined-immunodeficiency disorder characterized by a triad of thrombocytopenia, eczema, and immunodeficiency. Patients with WAS are also predisposed to autoimmunity and malignancy. Autoimmune manifestations have been reported in 26%–72% of patients with WAS. Autoimmunity is an independent predictor of poor prognosis and predisposes to malignancy. Development of autoimmunity is also an early pointer of the need for hematopoietic stem–cell transplantation. In this manuscript, we have collated the published data and present a narrative review on autoimmune manifestations in WAS. A summary of currently proposed immunopathogenic mechanisms and genetic variants associated with development of autoimmunity in WAS is also included.

Neoclassical Music in America: Voices of Clarity and Restraint. By R. James Tobin

As the twentieth century recedes, its history changes, and chroniclers attempting to propose continuities between what happened during its course and what has happened since are obliged to question received terminologies and categorizations, even as they strive to preserve them. With art music, the continued prominence of pre-1900 composers preserves the currency of such categories as Baroque, Classical, and Romantic; but derivatives of these—like neoclassicism—that served useful purposes between 1900 and 2000 do not necessarily retain the viability they might once have had before more recent rethinkings of broader notions of classicism and its contradicting consequence, modernism. Such preliminaries would be difficult to avoid if the text under review presented itself as a scholarly history of American neoclassicism, seeking to establish what this shares with neoclassicism in general, and how it differs from both classicism and modernism. But just as history changes, so does publishing. Rowan & Littlefield’s series, Modern Traditionalist Classical Music, of which R. James Tobin’s book is the second volume, comes across more as autobiography than musicology, with personal testimony and advocacy looming much larger than scholarly criticism and analysis. Contrast Joseph N. Straus’s Twelve-Tone Music in America (Cambridge, 2009), which briefly surveys three of Tobin’s favoured composers under the heading ‘some serial neoclassicists, tonalists, jazzers, and minimalists’. In just twelve pages Straus discusses Arthur Berger, Irvine Fine, and Louise Talma, with annotated music examples to ease the reader’s task in evaluating this unfamiliar music. Tobin has plentiful references to (often deleted) recordings but no score extracts, and as his subtitle suggests, he is much more at ease reflecting on the character of the compositions he introduces than in defining or dissecting their technical devices. As for autobiography, Tobin (b. 1937) provides an early pointer: ‘this book is dedicated to the memory of Harold Shapero [1920–13] because for half a century his Symphony for Classical Orchestra [1947] has had my highest admiration, and because it represents a central and constant touchstone of my personal musical taste’ (p. x).

The empirical relationship between success factors and dimensions

PurposeThe purpose of this paper is to report on a PhD thesis that examined the empirical relationship between a specific set of critical success factors (CSFs), project success, and success dimensions (criteria) from the perspectives of World Bank project supervisors (task managers or task team leaders) and project managers (the national project coordinators). Also, the PhD thesis author's journey and motivation are explained.Design/methodology/approachData were collected by web questionnaires addressed to 1,421 World Bank task team leaders and paper‐based questionnaires delivered to 600 national project coordinators in 26 different countries in Africa. Principal component and confirmatory factor analyses, multiple correlation and regression analyses, as well as structural equation models were used for data analysis in this study.FindingsFirst, research findings highlight a specific set of World Bank project CSFs (monitoring, coordination, design, training) and the existence of a second‐order latent CSF, that is World Bank project supervision. Second, they suggest that World Bank project supervision has differing significant influences on the two project success dimensions and that the first (project management (PM) success) does not significantly affect the second (deliverable success). Third, consistent with theory and practice, they suggest that the most prominent CSFs for both World Bank project supervisors and managers are design and monitoring. Fourth, they suggest that for the national project coordinators, project success is insensitive to the level of design efforts but a significant correlation does exist between monitoring efforts and project “profile”, a success dimension which is an early pointer of long‐term deliverable success (impact).Originality/valueThis study offers insights into the relationship between success factors and dimensions for ID projects with the perspectives of both the World Bank project supervisors and managers. The thesis calls for further research on PM in the ID industry sector.

Localized convexity subarachnoid haemorrhage – a sign of early cerebral venous sinus thrombosis

The diagnosis of cerebral venous sinus thrombosis (CVST) requires a high index of suspicion owing to the wide spectrum of clinical manifestations. Amongst the different presentations, radiological evidence of subarachnoid haemorrhage (SAH) often leads to diagnostic errors. Between March 2005 and December 2007, 233 patients with CVST were reviewed at our centre, and this report summarizes 10 cases that presented with SAH. The early clinico-radiological pointers towards a diagnosis of CVST are highlighted and previously published reports are reviewed. The mean age at presentation was 33 years (range 25-50), and the median duration from onset of symptoms to admission was 5 days (range 2-15). In all cases, there was radiological evidence of SAH with or without associated parenchymal bleeding or other signs of CVST. SAH was usually localized, involving the sulci of the cerebral convexity and sparing the basal cisterns. Aetiologically, there were two cases with both hyperhomocysteinaemia and polycythaemia and one case each of antiphospholipid antibody (APLA) syndrome, post-partum state, oral contraceptive use and dehydration because of diarrhoea. Eight patients improved with anticoagulant therapy despite the presence of SAH. Localized SAH (whether focal, unilateral or bilateral), especially when confined to the parasagittal or dorsolateral convexity of the brain and without involvement of the basal cisterns, may provide an early pointer towards an underlying CVST. The presence of predisposing factors for CVST accords a further diagnostic hint.

Predictive testing and population screening

Historically, medicine has focused on the treatment of disease. The aims were to diagnose the clinical problem, cure if possible and alleviate suffering where cure was not possible. While these still remain fundamental aims in health care, there has been an increasing focus on the prevention of disease and disability, including identification of syndromes or disease in the preclinical stages, and at-risk individuals or groups, with early intervention to reduce morbidity and mortality. There are several reasons for this shift in focus. Conceptually, if the goal of medicine is to relieve suffering from disease then prevention of disease, or at least long-term complications of disease, must be a key objective. Increasing medical knowledge and technology now provides the means to identify early pointers to future disease, including identification of genetic predispositions and other risk factors and better imaging techniques for early diagnosis, for a wide range of conditions. For health policy-makers, the potential economic efficiency gained by preventing disease and reducing the cost of treatment is also a contributing factor. However, strategies for preventing disease engender their own potential harms and there has been debate in both the academic and public arena about the ethical aspects of such programmes. In this Five-Minute Focus (FMF), the ethical issues raised by the strategy of predictive testing and population screening for disease are considered. Screening can be broadly divided into whole population screening and screening of at-risk groups. Further, categorization according to the nature of the condition being screened for or the screening subjects can be made and includes the overlapping categories listed below. Predictive testing, for example genetic testing for Huntington's Disease, focuses on individuals and includes testing for conditions for which there may be no effective treatment. Screening for conditions that only affect the person being screened. For example, cervical cytology screening, mammography screening, cardiovascular risk assessment; screening for conditions which can be transmitted to others, for example, HIV testing or screening for TB; screening for genetically-determined conditions which have implications for other family members; screening those who are unable to give consent to screening, for example neonatal screening for metabolic diseases; screening embryos and fetuses. Antenatal and pre-implantation screening are not considered here as this merits more detailed discussion in a future FMF.

How Good at Neurology are you? – Questions

1. Consider the following case. A 44-year-old lady presented with frontal headaches. She had a past medical history of a breast lump and she had an uncle with epilepsy. She...

Intima media thickness of the carotid arteries: early pointer to arteriosclerosis and therapeutic endpoint

An early sign of atherosclerosis is hypertrophy of the arterial wall. Increased intima-media thickness (IMT) is a non-invasive marker of arterial wall alteration, which can easily be assessed in the carotid arteries by high-resolution B-mode ultrasound. There are important differences in B-mode measurements of carotid IMT between laboratories. These might concern on IMT image acquisition (in relation to the segment and/or the wall of measure) as well as determination of the echo boundary defining the IMT interfaces and the difference in relationship between anatomic and sonographic structures of the near and far arterial wall. Measurements derived from the near wall reflect thickness of a part of media and intima influenced by sonographic artefacts, rather than that of the total intima-media complex. Two main approaches are used for measuring IMT: 1) manual measurement at multiple extracranial carotid sites in near and far walls, and 2) automated computerized measurement, restricted to the far wall of the distal common carotid artery. Intra- and inter-observer variabilities have been found to vary in manual measurements between 0.09 to 0.13 mm and 0.12 to 0.18 mm (absolute differences). The best reproducibility of manual IMT-measurements is found at the far wall of the common carotid artery 1 cm from the bulb in the site of two parallel wall contours without local thickening. For automated measurements lower intra- and inter-observer variabilities have been reported. IMT of the common carotid artery is strongly influenced by age. For younger age groups (20 to 30 years) mean IMT values of 0.5 mm have been reported, while IMT values of 0.9 mm have been found for older subjects (60 to 70 years). Carotid IMT correlates with other risk factors such as systolic blood pressure, serum lipids and smoking, as well as being positively linked to the presence and extend of coronary artery disease in both women and men. The demonstration of a correlation between IMT and cardiovascular events such as stroke and myocardial infarction in clinical studies of atherosclerosis progression and cardiovascular outcomes have led to FDA accepting 2D ultrasound as a valid technique in clinical studies of atherosclerosis. Regression or slowing of progression of increased carotid IMT by various antihypertensive and lipid-lowering drugs agents have been reported. In addition to carotid IMT measurement as a predictive value of future vascular events the presence of plaques or stenosis in the carotid artery tree increases drastically the risk for cardiovascular events. Therefore the authors of this article propose the use of high resolution Duplex-Sonography for the assessment IMT of the common carotid artery as well as the detection of plaques and stenosis in clinical practice. In conclusion, high-resolution Duplex-sonography seems promising for the detection, quantification and serial investigations of structural alterations of the arterial wall. The method is sensitive enough to be applied in clinical studies of the progression and regression of early preintrusive atherosclerotic lesions in extracranial carotid arteries. Moreover IMT of the common carotid artery can be used as a therapeutic endpoint.

The Knowledge Adventure

The Knowledge Adventure

Herpes zoster ophthalmicus: an early pointer to HIV-1 positivity in young African patients.

We studied prospectively 30 patients, seen over 10 months, who had herpes zoster ophthalmicus (HZO) and who were classified by age, sex, ophthalmological observations and HIV-1 status. Of patients who presented with HZO, 40% were HIV positive, and the majority were less than 40 years of age. The clinical manifestation of HZO has a high positive predictive value for HIV positivity in young patients with this viral infection.

STRIATONIGRAL DEGENERATION

The clinical and pathological features of 10 cases of striatonigral degeneration are described: 5 were misdiagnosed in life as Parkinson's disease. Retrospectively, helpful early pointers to the diagnosis in these cases included unexplained falls, autonomic dysfunction, absence of rest tremor and failure to respond to L-dopa, but these were not always present. The pathological diagnosis could not be excluded on macroscopic examination of the striatum. Relative preservation of the putamen occurred in the 4 patients who benefited from L-dopa. The caudate nucleus was involved in all cases and there was no sparing of the large striatal neurons. In mild cases, involvement of the putamen was confined to its posterior two-thirds, dorsolaterally. With increasing severity this extended in a dorsal to ventral and posterior to anterior direction. Seven of the cases had evidence of olivopontocerebellar damage, but only 2 of these had clinical evidence of cerebellar disease. Correlation was found between the neuronal counts in caudate:putamen, striatum:nigra compacta, globus pallidus:nigra compacta, nigra compacta:locus coeruleus. The most severely involved part of the substantia nigra pars compacta was the ventrolateral zone, which projects to the dorsal putamen, the earliest site of striatal disease.

Amyloid and amyloidosis

Cutaneous lesions are present in up to 40% of patients with primary and myeloma-associated systemic amyloidosis and occur as a result of tissue deposition of immunoglobulin light chain material derived from a circulating paraprotein. The occurrence of waxy, purpuric mucocutaneous lesions provides a crucial early pointer to underlying occult plasma cell dyscrasia; the combination of the symptoms of the carpal tunnel syndrome, macroglossia, and specific mucocutaneous lesions is highly characteristic. Although secondary systemic (reactive) amyloidosis rarely gives rise to clinically evident cutaneous lesions, it may be etiologically related to a number of chronic dermatoses. Lesions of nodular primary localized cutaneous amyloidosis are indistinguishable from those of primary and myeloma-associated systemic amyloidosis, and they result from local plasma cell infiltration. Macular and papular (lichen amyloidosus) variants of primary localized cutaneous amyloidosis may have a familial or racial basis and are characterized by a tendency for keratinocytes to undergo filamentous degeneration and apoptosis. The prognosis of patients with plasma cell dyscrasia-related systemic amyloidosis remains poor, since there is little response to therapy with cytotoxic agents, colchicine, or dimethylsulfoxide. Colchicine is the drug of choice in the prevention and treatment of the renal amyloidosis associated with familial Mediterranean fever, and dimethylsulfoxide may be useful in the management of patients with secondary systemic amyloidosis. Macular amyloid and lichen amyloidosus generally follow a chronic course with intractable pruritus; there have been isolated reports of the beneficial effect of dermabrasion, topical dimethylsulfoxide, and therapy with the aromatic retinoid, etretinate.

The chest film findings in ‘Q’ fever — A series of 35 cases

Thirty-five cases of 'Q' fever have been admitted and confirmed serologically over the past 20 years. Thirty-two of these cases had chest films on admission, and lung changes were present in 87%. The lung changes were: 1. Multiple round segmental consolidations, 5--10 cm in diameter, of ground glass density and usually situated in the lower lobes. 2. Linear atelectasis. 3. Lobar or partial lobar consolidation, with some loss of volume in the affected lobe. 4. A slight pleural reaction in a few cases. 5. Some cases had background emphysema of the lungs. All the lesions tended to be slow to clear. The resolution time was from 10 to 70 days, with an average time fo 30 days. Some of the segmental lesions became small, round and dense during resolution. The 35 cases were almost exclusively in males. The finding of a single or multiple round segmental opacities of ground glass density, as described, especially with linear atelectasis, was found to be good evidence that the patient had 'Q' fever. The point is made that the admission chest film is in some cases a very useful early pointer to the diagnosis. This allows specific chemotherapy to be started before the serological results have come back. Plate atelectasis was helpful as a distinguishing feature from primary atypical pneumonia.