La 18F-FDG PET/TC ayuda a desenmascarar a la gran imitadora: un caso de neurosarcoidosis con implicación aislada en la médula espinal / 18F-FDG PET/CT helps in unmasking the great mimicker: a case of neurosarcoidosis with isolated involvement of the spinal cord

Durante 4 semanas, un paciente varón de 36 años, sin historial clínico de relevancia, presentó entumecimiento en las extremidades inferiores, inestabilidad al andar, retención de orina y estreñimiento. La RM de la médula espinal mostró edema difuso en la médula dorsal cervicotorácica, así como imágenes de lesiones intramedulares sólidas indicativas de metástasis. Se realizó una 18F-FDG PET/TC para identificar la malignidad primaria de los focos hipermetabólicos dentro de la médula cervicotorácica, así como la leve linfoadenopatía hiliar bilateral hipermetabólica y los nódulos pulmonares hipermetabólicos indicativos de sarcoidosis frente a metástasis. El diagnóstico de sarcoidosis fue respaldado al identificarse un granuloma no caseificante en la biopsia del nódulo pulmonar. El paciente respondió bien al tratamiento con esteroides y los síntomas desaparecieron en 3 semanas

A 36 year-old male with no significant past medical history presented with lower extremity numbness, gait instability, and urinary and bowel retention of 4 weeks onset. Spine MRI revealed diffuse oedema of cervicothoracic spinal cord with several solid enhancing intramedullary lesions, suggestive of metastases. The 18F-FDG PET/CT performed to identify the primary malignancy demonstrated mild hypermetabolic foci within the cervicothoracic cord, as well as a mildly hypermetabolic bilateral hilar lymphadenopathy and a mildly hypermetabolic pulmonary nodule, suggestive of sarcoidosis versus metastasis. The diagnosis of sarcoidosis was supported by identifying non-caseating granuloma in the biopsy of the pulmonary nodule. The patient responded well to steroid-therapy, with the symptoms being resolved within 3 weeks

Recognition and management of acute kidney injury in children: The ISN 0by25 Global Snapshot study.

BACKGROUND: In low and middle-income countries, reliable data on the epidemiology of childhood acute kidney injury (AKI) is lacking. The Global Snapshot, conducted by the ISN "0by25" AKI initiative, was a world-wide cross-sectional, observational study to evaluate AKI in hospitalized patients. Here we report the pediatric results of this study. PATIENTS AND METHODS: We prospectively collected data on children who met the Kidney Disease Improving Global Outcomes AKI criteria during a 10-week window in late 2014. AKI risk factors, etiological factors, management and outcomes were recorded using standardized forms and protocols. Countries were classified according to their 2014 gross national income (GNI) per person into high-income countries (HIC), upper-middle income countries (UMIC) and low and low-middle income countries (LLMIC). Need for renal replacement therapy, mortality, and renal recovery were assessed 7 days after AKI diagnosis or at hospital discharge, whichever came first. RESULTS: 92 centers from 41 countries collected data on 354 pediatric AKI patients; 53% of the children developed AKI while hospitalized and 47% in the community. The most common etiological factors for AKI differed across GNI categories as well as between patients with community-acquired vs. hospital-acquired AKI. Children from HIC were younger, and larger proportion of AKI in this group were due to post-surgical complications vs. other etiologies when compared to other income categories. In patients with hypotension as the cause of AKI, the adjusted risk of death was almost 10-fold higher compared to patients without hypotension as an etiological factor for AKI development. Mortality was similar within AKI stages in HIC and UMIC. In LLMIC, patients with the highest AKI level of severity had higher mortality than patients in higher income categories. Patients from LLMIC and UMIC had a 57-fold and 11 fold higher adjusted risk of death, respectively, compared to patients from HIC. CONCLUSION: In resource-limited countries, pediatric AKI-associated mortality is disproportionately higher when compared to high-resource areas, especially among patients with more severe AKI.

18F-FDG PET/CT helps in unmasking the great mimicker: A case of neurosarcoidosis with isolated involvement of the spinal cord. / La 18F-FDG PET/TC ayuda a desenmascarar a la gran imitadora: un caso de neurosarcoidosis con implicación aislada en la médula espinal.

A 36 year-old male with no significant past medical history presented with lower extremity numbness, gait instability, and urinary and bowel retention of 4 weeks onset. Spine MRI revealed diffuse oedema of cervicothoracic spinal cord with several solid enhancing intramedullary lesions, suggestive of metastases. The 18F-FDG PET/CT performed to identify the primary malignancy demonstrated mild hypermetabolic foci within the cervicothoracic cord, as well as a mildly hypermetabolic bilateral hilar lymphadenopathy and a mildly hypermetabolic pulmonary nodule, suggestive of sarcoidosis versus metastasis. The diagnosis of sarcoidosis was supported by identifying non-caseating granuloma in the biopsy of the pulmonary nodule. The patient responded well to steroid-therapy, with the symptoms being resolved within 3 weeks.

Comprehensive population screening in the Ashkenazi Jewish population for recurrent disease-causing variants.

The Ashkenazi Jewish (AJ) population has an increased risk for a variety of recessive diseases due to historical founder effects and genetic drift. For some, the disease-causing founder mutations have been identified and well-characterized, but for others, further study is necessary. The purpose of this study is to assess the carrier frequencies of 85 pathogenic variants causative of 29 recessive conditions in the AJ population. Up to 3000 AJ individuals were genotyped by Luminex MagPlex® -TAG™ bead array or Agena Bioscience™ MassARRAY assays. We identified seven conditions with carrier frequencies higher than 1 in 100, nine between 1 in 100 and 1 in 200, and four between 1 in 200 and 1 in 500. Variants in nine conditions had a detected carrier rate of less than 1 in 500 or were not identified in approximately 2000 AJ individuals. We assessed the combined AJ carrier frequency for 18 relatively prevalent diseases to be 1 in 6, and the risk of AJ individuals to be a carrier couple for one of these 18 diseases as 1 in 441. We note additional recessive genetic conditions should be considered for AJ carrier screening panels.

Carrier screening of RTEL1 mutations in the Ashkenazi Jewish population.

Hoyeraal-Hreidarsson syndrome (HH) is a clinically severe variant of dyskeratosis congenita (DC), characterized by cerebellar hypoplasia, microcephaly, intrauterine growth retardation, and severe immunodeficiency in addition to features of DC. Germline mutations in the RTEL1 gene have recently been identified as causative of HH. In this study, the carrier frequency for five RTEL1 mutations that occurred in individuals of Ashkenazi Jewish descent was investigated in order to advise on including them in existing clinical mutation panels for this population. Our screening showed that the carrier frequency for c.3791G>A (p.R1264H) was higher than expected, 1% in the Ashkenazi Orthodox and 0.45% in the general Ashkenazi Jewish population. Haplotype analyses suggested the presence of a common founder. We recommend that the c.3791G>A RTEL1 mutation be considered for inclusion in carrier screening panels in the Ashkenazi population.

A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population.

Alport syndrome is an inherited progressive nephropathy arising from mutations in the type IV collagen genes, COL4A3, COL4A4, and COL4A5. Symptoms also include sensorineural hearing loss and ocular lesions. We determined the molecular basis of Alport syndrome in a non-consanguineous Ashkenazi Jewish family with multiple affected females using linkage analysis and next generation sequencing. We identified a homozygous COL4A3 mutation, c.40_63del, in affected individuals with mutant alleles inherited from each parent on partially conserved haplotypes. Large-scale population screening of 2017 unrelated Ashkenazi Jewish samples revealed a carrier frequency of 1 in 183 indicating that COL4A3 c.40_63del is a founder mutation which may be a common cause of Alport syndrome in this population. Additionally, we determined that heterozygous mutation carriers in this family do not meet criteria for a diagnosis of Thin Basement Membrane Nephropathy and concluded that carriers of c.40_63del are not likely to develop benign familial hematuria.

Scope and limitations of therapies: a neomillennial epistemological evaluation for helping medical practices.

Medical practice is in crisis - the sophistications are enormous and expensive, and the outcomes leave much to be desired. An epistemologic evaluation that weighs the scope and limitations of any -pathy or any procedure seems to be the need of the day. As an example, described herein is the logic of such an exercise; and a sample of the exercise itself, taking cancer as an example.

Cost-effectiveness of disease-modifying therapy for multiple sclerosis: a population-based study.

OBJECTIVE: To evaluate the cost-effectiveness of disease-modifying therapies (DMTs) in the United States compared to basic supportive therapy without DMT for patients with relapsing multiple sclerosis (MS). METHODS: Using data from a longitudinal MS survey, we generated 10-year disease progression paths for an MS cohort. We used first-order annual Markov models to estimate transitional probabilities. Costs associated with losses of employment were obtained from the Bureau of Labor Statistics. Medical costs were estimated using the Centers for Medicare and Medicaid Services reimbursement rates and other sources. Outcomes were measured as gains in quality-adjusted life-years (QALY) and relapse-free years. Monte Carlo simulations, resampling methods, and sensitivity analyses were conducted to evaluate model uncertainty. RESULTS: Using DMT for 10 years resulted in modest health gains for all DMTs compared to treatment without DMT (0.082 QALY or <1 quality-adjusted month gain for glatiramer acetate, and 0.126-0.192 QALY gain for interferons). The cost-effectiveness of all DMTs far exceeded $800,000/QALY. Reducing the cost of DMTs had by far the greatest impact on the cost-effectiveness of these treatments (e.g., cost reduction by 67% would improve the probability of Avonex being cost-effective at $164,000/QALY to 50%). Compared to treating patients with all levels of disease, starting DMT earlier was associated with a lower (more favorable) incremental cost-effectiveness ratio compared to initiating treatment at any disease state. CONCLUSION: Use of DMT in MS results in health gains that come at a very high cost.

Proof of concept studies for tissue-protective agents in multiple sclerosis.

BACKGROUND: There is considerable interest in tissue-protective treatments for multiple sclerosis (MS). METHODS AND OBJECTIVES: We convened a group of MS clinical trialists and related researchers to discuss designs for proof of concept studies utilizing currently available data and assessment methods. RESULTS: Our favored design was a randomized, double-blind, parallel-group study of active treatment versus placebo focusing on changes in brain volume from a post-baseline scan (3-6 months after starting treatment) to the final visit 1 year later. Study designs aimed at reducing residual deficits following acute exacerbations are less straightforward, depending greatly on the anticipated rapidity of treatment effect onset. CONCLUSIONS: The next step would be to perform one or more studies of potential tissue-protective agents with these designs in mind, creating the longitudinal data necessary to refine endpoint selection, eligibility criteria, and sample size estimates for future trials.

Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease.

PURPOSE: A clinical trial was conducted to evaluate the safety and efficacy of alglucosidase alfa in infants and children with advanced Pompe disease. METHODS: Open-label, multicenter study of IV alglucosidase alfa treatment in 21 infants 3-43 months old (median 13 months) with minimal acid alpha-glucosidase activity and abnormal left ventricular mass index by echocardiography. Patients received IV alglucosidase alfa every 2 weeks for up to 168 weeks (median 120 weeks). Survival results were compared with an untreated reference cohort. RESULTS: At study end, 71% (15/21) of patients were alive and 44% (7/16) of invasive-ventilator free patients remained so. Compared with the untreated reference cohort, alglucosidase alfa reduced the risk of death by 79% (P < 0.001) and the risk of invasive ventilation by 58% (P = 0.02). Left ventricular mass index improved or remained normal in all patients evaluated beyond 12 weeks; 62% (13/21) achieved new motor milestones. Five patients were walking independently at the end of the study and 86% (18/21) gained functional independence skills. Overall, 52% (11/21) of patients experienced infusion-associated reactions; 95% (19/20) developed IgG antibodies to recombinant human lysosomal acid alpha-glucosidase; no patients withdrew from the study because of safety concerns. CONCLUSIONS: In this population of infants with advanced disease, biweekly infusions with alglucosidase alfa prolonged survival and invasive ventilation-free survival. Treatment also improved indices of cardiomyopathy, motor skills, and functional independence.

A community genetics approach to population screening in India for mental retardation--a model for developing countries.

Some 0.55 million people living in semi-urban and slum populations were screened for mental retardation by trained primary health centre (PHC) doctors, nurses and community health volunteers (CHVs). The staff were provided with prior training on the detection, prevention and diagnosis of mental retardation, prenatal diagnosis, and reproductive responsibilities. Field visits were employed to confirm diagnosed developmental disabilities, and demographic data incorporating social maps of 14 PHCs were prepared. Cases with high-risk genetic factors detected by PHC staff were referred to the Centre for Research in Mental Retardation (CREMERE) for cytogenetic and metabolic investigations, thus linking the study population and the Referral Centre. A genetic team interacted with the patient and family members for genetic counselling. Mental retardation was confirmed in 511 of the 525 cases reported, reflecting the positive impact of training on the CHVs. Potentially preventable environmental factors, such as birth asphyxia, infections, and low birth weight were identified in 251 cases (49%), 137 (27%) of which had additional genetic factors. Genetic causes were found in 186 (36%) individuals, the most common being Down syndrome. The study illustrates the urgent need for the integration of genetic screening into the public health services in India.

Photocatalytic degradation of trans-cinnamic, dihydrocinnamic, trans-caffeic, and dihydrocaffeic acids and characterization of the products.

Catalysed degradation of aqueous solutions of cinnamic 1, dihydrocinnamic 2, dihydrocaffeic 3 and trans-caffeic 4 acids in the presence of (TiO2) and UV radiation and the products identified by HPLC, and after treatment with diazomethane by GC-MS have been studied. A pH range of 3 to 11 was used. The four acids, in the presence of TiO2 in the dark, underwent little degradation. Extended irradiation of all the acids in the presence of TiO2 produced complete degradation as shown by TOC measurements. Initially the volume of carbon dioxide produced rose steadily to a constant value.

Chemical kinetics of the photocatalytic degradation of trans-cinnamic, dihydrocinnamic, trans-caffeic, and dihydrocaffeic acids.

Quantitative studies of the catalysed degradation of aqueous solutions of cinnamic 1, dihydrocinnamic 2, trans-caffeic 3 and dihydrocaffeic 4 acids in the presence of TiO2 and UV radiation at pH 3 and 10 are reported. The phenolic and aliphatic unsaturated groups in caffeic acid 3 caused it to be adsorbed more strongly than the phenolic saturated acid 4, and these two acids were much more strongly adsorbed than cinnamic and hydrocinnamic acids. The kinetics of the degradation of each acid has been studied at pH 3 and 10. TIC analysis showed complete mineralisation of the acids after 9 h.

Non-pathology: the bedrock of pathology.

Pathology, also called morbid anatomy, is macroscopically, microscopically, and molecularly so manifest an array of phenomena that it has compelled medical men to closely link it up with disease, dis-ease, and death. But there is more than meets the eye of the morbid anatomists, microscopists, and the molecular biologists. The obvious science of pathology is governed by numerous abstract, subtle, non-pathological factors. A pathological phenomenon is subservient to cosmic noumenon. Such a sea-change allows a newer perspective that cures modern medicine of many of its dogmas and provides epistemologically valid directions to research methodologies on the one hand and clinical practices on the other.

Synthesis, hydroxyl radical production and cytotoxicity of analogues of bleomycin.

Two pyridine analogues of the metal complexing region of the anticancer drug bleomycin and two related but deactivated prodrugs have been linked to a 2,6-diphenylpyridine derivative as a DNA binding unit. The 2,6-diphenylpyridine system is structurally related to known amplifiers of the cytotoxicity of bleomycin. The conjugates were found to bind to DNA more strongly than bleomycin-A2 and were more cytotoxic than the corresponding compounds lacking the DNA binding unit. On exposure of a mixture of cells and prodrugs to hypoxia and then air, the prodrug containing the nitrohistidine unit was not bioreductively activated but the prodrug having an N-oxide group was bioreductively activated. This result represents a novel approach to the improvement of the therapeutic ratio of bleomycin analogues.

Cause of death--so-called designed event acclimaxing timed happenings.

Cause-of-death as an established global medical institution faces its greatest challenge in the commonplace observation that the healthy do not necessarily survive and the diseased do not necessarily die. A logical analysis of the assumed relationships between disease and death provides some insights that allow questioning the taken-for-granted relationship between defined disease/s and the final common parameter of death. Causalism as a paradigm has taken leave of all advanced sciences. In medicine, it is lingering on for anthropocentric reasons. Natural death does not come to pass because of some (replaceable) missing element, but because the evolution of the individual from womb to tomb has arrived at its final destination. To accept death as a physiologic event is to advance thanatology and to disburden medical colleges and hospitals of a lot of avoidable thinking and doing.