ABSTRACT
Small osteolabral avulsions of the hip can be easily missed, and postreduction stress testing and a computed tomography (CT) scan of the hip should be done to look for these injuries. The usual modality of treatment of these unstable osteolabral avulsions is suture anchors, Herbert screws or spring plates. But when the bony avulsion is small, the use of these implants becomes a tedious job. We present a novel technique of fixing small osteochondral avulsion fractures not amenable to fixation using screws or spring plates. We performed a retrospective analysis of 57 cases of patients who underwent open reduction and internal fixation for posterior fracture dislocation of the acetabulum, and we identified 6 cases of small posterior labral osteochondral fragments leading to instability. These injuries were fixed using a novelmethod. Themean Harris Hip Score at the final follow-up was of 92.5. Fixation of osteochondral avulsions associated with posterior hip fracture dislocation can be a difficult task if the bony fragment is small. Our technique is a simple, cost-effective and reliable way of fixing such avulsions with satisfactory outcomes.
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BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. METHODS: MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 µg/kg, then escalated to 570 µg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. FINDINGS: Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 µmol/L (95% CI -257 to -94) for maralixibat versus 11 µmol/L (-58 to 80) for placebo, also representing a significant difference of -187 µmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. INTERPRETATION: Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. FUNDING: Mirum Pharmaceuticals.
Subject(s)
Cholestasis, Intrahepatic , Pruritus , Humans , Double-Blind Method , Male , Female , Cholestasis, Intrahepatic/drug therapy , Cholestasis, Intrahepatic/blood , Child , Adolescent , Child, Preschool , Infant , Pruritus/etiology , Pruritus/drug therapy , Treatment Outcome , ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics , ATP Binding Cassette Transporter, Subfamily B/deficiencyABSTRACT
ABSTRACT: Cryptococcosis usually occurs in immunocompromised patients and presents as meningitis and lung disease. Adrenal gland involvement may be observed, yet primary adrenal insufficiency by cryptococcal infection is infrequent. We present a case of a middle-aged immunocompetent man with primary adrenal insufficiency and bilateral adrenal lesions, splenomegaly, and miliary mottling in the lungs on imaging. No evidence of meningitis was witnessed. The clinico-radiological findings led toward the differential diagnosis of disseminated tuberculosis or fungal infection. Detection of cryptococcus organism was done on fine-needle aspiration cytology and biopsy on periodic acid-Schiff stain and Gomori`s methenamine silver stain. Thus, it is recommended to keep the possibility of cryptococcosis in mind while dealing with instances that have a tuberculosis-like clinico-radiological presentation. The detection of the causal organism on Fine needle aspiration (FNA)/biopsy examination may be useful in confirming the diagnosis and determining the appropriate medical treatment.
Subject(s)
Adrenal Glands , Adrenal Insufficiency , Cryptococcosis , Humans , Male , Cryptococcosis/diagnosis , Cryptococcosis/drug therapy , Cryptococcosis/pathology , Biopsy, Fine-Needle , Adrenal Insufficiency/diagnosis , Middle Aged , Adrenal Glands/pathology , Adrenal Glands/diagnostic imaging , Adrenal Glands/microbiology , Cryptococcus/isolation & purification , Diagnosis, Differential , Tomography, X-Ray Computed , Lung/pathology , Lung/diagnostic imaging , Microscopy , Adrenal Gland Diseases/diagnosis , Adrenal Gland Diseases/microbiology , Immunocompetence , HistocytochemistryABSTRACT
Hypercalcemia-induced pancreatitis is a rare and challenging complication, particularly when secondary to sarcoidosis. This case report discusses the clinical presentation, diagnostic workup, and management of a 61-year-old patient diagnosed with hypercalcemia-induced pancreatitis secondary to sarcoidosis. The abstract highlights the complexities of diagnosing pancreatitis linked to elevated calcium levels and underscores the importance of recognizing underlying conditions such as sarcoidosis in these cases. Through this case, we aim to enhance awareness among clinicians regarding the association between sarcoidosis, hypercalcemia, and pancreatitis, ultimately contributing to improved diagnostic accuracy and patient care strategies.
ABSTRACT
Hypercalcemia is a complex medical condition characterized by elevated levels of serum calcium (>10.5 mg/dL) in the bloodstream, often arising from various underlying etiologies. This condition presents a significant clinical challenge due to its diverse clinical manifestations and potential for serious complications. Profiling and understanding hypercalcemia is essential for accurate diagnosis, appropriate management, and improved patient outcomes. In this study, we delve into the comprehensive profiling of hypercalcemia, encompassing its epidemiology, pathophysiology, clinical presentation, and diagnostic approaches. We explore the multifaceted etiological factors contributing to hypercalcemia, including primary hyperparathyroidism, malignancies, granulomatous disorders, medications, and more. We highlight the intricate interplay between parathyroid hormone, vitamin D, and other regulatory mechanisms that influence calcium homeostasis, shedding light on the underlying molecular pathways. Furthermore, we discuss the diverse clinical manifestations of hypercalcemia, ranging from asymptomatic cases to severe, life-threatening complications involving the renal, gastrointestinal, cardiovascular, and neuromuscular systems. Accurate diagnosis is pivotal, and we evaluate the array of laboratory tests, imaging modalities, and specialized assays that aid in identifying the root cause of hypercalcemia. We emphasize the importance of a systematic approach to differential diagnosis and the significance of risk stratification to guide clinical decision-making. The evolving landscape of treatment options for hypercalcemia is also explored, encompassing both acute management and long-term strategies tailored to the underlying etiology. We assess the role of hydration, pharmacological agents, and surgical interventions, underscoring the need for individualized therapeutic plans based on the severity and underlying cause of hypercalcemia. In conclusion, the profiling of hypercalcemia is a multidimensional endeavor that necessitates a comprehensive understanding of its underlying mechanisms, diverse clinical presentations, and diagnostic intricacies. This study intends to serve as a valuable resource for healthcare professionals, offering insights into the complex terrain of hypercalcemia.
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BACKGROUND AND OBJECTIVE: Hyponatremia is the most common electrolyte abnormality encountered in a hospital setting, and the data regarding the contribution of hyponatremia to overall mortality are conflicting. The study objective was to determine patients' clinical profiles and outcomes with hyponatremia. METHODS: This prospective cross-sectional study was conducted at Dayanand Medical College and Hospital, Ludhiana, and included 375 adult patients aged more than 18 years with a confirmed diagnosis of hyponatremia. Patients were subdivided into three groups based on the severity of hyponatremia: mild (130-135 mmol/L), moderate (125-129 mmol/L), and profound (<125 mmol/L). RESULTS: The most common symptom was confusion (57.3%) followed by deep somnolence (40%) and nausea (36.8%). The most common cause of hyponatremia was diuretics (30.7%), followed by the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (17.8%) and chronic liver disease (CLD) (14.1%). The severity of hyponatremia did not significantly influence the outcome. Patients with CLD and chronic kidney disease (CKD) as the etiology of hyponatremia had significantly worse outcomes compared to other causes of hyponatremia. The most common type was hypovolemic hypotonic followed by euvolemic hypotonic and hypervolemia hypotonic hyponatremia. Nearly half of the total deaths were observed in the hypervolemic hyponatremia group and were significantly higher compared to the other two groups (p=0.001). Correction of hyponatremia (i.e., serum sodium >135 mmol/L) was significantly linked with good outcomes (p=0.003). CONCLUSION: Our study showed that the etiology of hyponatremia was a more important prognostic indicator rather than the severity of hyponatremia. Normalization of serum sodium was associated with improved survival.
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Insulin autoimmune syndrome [IAS, Hirata disease (HD)] is a rare cause of recurrent spontaneous hypoglycemic episodes, characterized by high serum insulin levels and high titers of autoantibodies against endogenous insulin. We report a case of a previously healthy Indian male presenting with recurrent episodes of hypoglycemia with no prior exposure to exogenous insulin. Regular glucose monitoring was done. Laboratory tests showed insulin >1000 µIU/mL and C-peptide levels of 12.8 ng/ml. The patient had high titers of insulin autoantibodies (IAA) (>100 units/mL; normal range: <10 units/mL), which indicated a diagnosis of IAS. The patient was consuming alpha-lipoic acid; sulfhydryl-containing compounds have been linked to IAS. This case report highlights the importance of IAA titers in first-line investigations for hypoglycemia in a non-diabetic patient with strikingly high blood insulin levels and discusses the potential relationship between IAS and alpha-lipoic acid.
ABSTRACT
BACKGROUND: Takotsubo cardiomyopathy (TCM) is a rare disease entity characterized by acute, non-ischemic, reversible myocardial dysfunction that mimics acute myocardial infarction. Activation and excessive outflow of sympathetic nervous system are believed to be central to the figure in the disease pathogenesis. Adrenocortical hormones potentiate the systemic actions of sympathetic nervous system and accordingly are essential for regulation of myocardial function. We present an unusual case of a middle-aged woman with primary adrenal insufficiency who presented paradoxically with TCM. CASE PRESENTATION: A 50-year-old woman with past history of hypothyroidism presented to emergency department with history of acute chest pain and syncope. There was no significant drug history or history of an emotional or physical stimulus prior to admission. Prominent pigmentation over the tongue and skin creases of hands were noted. On presentation, she was in shock and had ventricular tachycardia which required electrical cardioversion. The subsequent electrocardiogram demonstrated diffuse T-wave inversions with prolonged QTC. There was apical hypokinesia on echocardiogram, and cardiac biomarkers were elevated. There was persistent inotropic requirement. She had marked postural symptoms, and a postural blood pressure drop of 50 mm Hg was present. Initial laboratory parameters were significant for hyperkalemia (7.8 mEq/L) and hyponatremia (128 mEq/L). These findings prompted evaluation for adrenal insufficiency which was confirmed with appropriate tests. Autoimmune polyendocrine syndrome II was thus diagnosed based on the above findings. Coronary angiography revealed normal coronaries. The diagnoses of TCM was established in accordance with the International Takotsubo Diagnostic Criteria. She was started on stress dose steroid replacement therapy and improved dramatically. At one month of follow-up, the patient is asymptomatic, and there was normalization of her left ventricular function. CONCLUSIONS: Intricate relationship and interplay exist between the steroid hormones and catecholamines in the pathogenesis of TCM. Steroid hormones not only potentiate the actions of catecholamines, but they also regulate and channelize catecholaminergic actions preventing their deleterious effects on the cardiac tissue. Hence, both steroid deficiency and exogenous steroid replacement may precipitate TCM. Evidence from more such cases and larger perspective studies in future will further improve our understanding of this complex disease process and its myriad associations.
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Background and Objectives: Diabetes mellitus is associated with poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19). This study aimed to explore the clinical characteristics of patients with type 2 diabetes with COVID-19, and to determine the impact of type 2 diabetes on clinical outcome of patients with COVID-19. Material and Methods: This single-center, retrospective, observational study enrolled patients admitted from March 2020 to June 2021 with COVID-19. The clinical and biochemical characteristics of patients with known type 2 diabetes, newly diagnosed diabetes, type 2 diabetes with comorbidities and those who succumbed to illness were analyzed. Results: Of 4,559 patients with COVID-19, 2,090 (45.8%) had type 2 diabetes. Patients with COVID-19 with diabetes were older, more likely to receive mechanical ventilation, had higher odds of mortality from COVID-19 as compared with patients without diabetes. In addition, patients with diabetes had significantly higher levels of serum creatinine, C-reactive protein, ferritin, lactate dehydrogenase, and D-dimer. Compared with previously diagnosed patients with diabetes, newly diagnosed patients had higher mortality (33% vs. 27%, P = 0.049). Among patients with COVID-19 and diabetes, nonsurvivors had significantly higher levels of inflammatory markers and had severe impairment of cardiac, renal, and coagulation parameters as opposed to survivors. Conclusion: Patients with COVID-19 with diabetes were more likely to have severe disease and had higher mortality. Presence of chronic kidney disease and coronary artery disease in patients with diabetes with COVID-19 was associated with adverse outcome. Patients with newly diagnosed diabetes had higher odds of severe disease at presentation and had higher mortality.
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CONTEXT: The effects of coronavirus disease 2019 (COVID-19) on the endocrine system remain uncertain. OBJECTIVE: Our study aimed to explore the possible effects of COVID-19 on endocrine organs and to determine the impact of glycemic status, 25-hydroxyvitamin D levels, calcium levels, and thyroid dysfunction on the final outcome of patients with COVID-19. DESIGN AND METHODS: This single-center, retrospective study evaluated endocrine function abnormalities in 102 patients hospitalized with COVID-19 in the intensive care unit (ICU). RESULTS: Of 102 patients admitted to ICU, 42 (41.2%) succumbed to illness. The most frequently observed abnormality in thyroid function tests was low free triiodothyronine (FT3) levels (56%). A thyroid profile indicating thyrotoxicosis was detected in five (4.9%) patients, and overt hypothyroidism was identified in two (1.9%) patients. New-onset diabetes was detected in five (4.9%) patients whereas diabetic ketoacidosis at presentation was found in six (5.9%) cases. Rhino-orbital mucormycosis was detected in one patient with diabetes during treatment of COVID-19 while three (2.9%) patients were diagnosed with pulmonary mucormycosis after recovery from COVID-19. Hypocalcemia was observed in 52 (51 %) patients. Out of 42 patients who died, 32 patients had low FT3, 26 patients had high glycated haemoglobin (HbA1c), and 33 patients had low 25-hydroxyvitamin D. Multivariate analysis demonstrated that low concentration of 25-hydroxyvitamin D, low FT3 and higher HbA1c levels were significantly associated with increased mortality. CONCLUSION: New-onset thyrotoxicosis in COVID-19 patients is mostly due to subacute thyroiditis. Hypocalcemia is also frequently encountered in patients with moderate disease and those with critical COVID-19. A high index of suspicion is required to timely diagnose mucormycosis in COVID-19 patients with diabetes.
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OBJECTIVE: To identify key epidemiologic factors relevant to fetal development that are associated with biliary atresia. STUDY DESIGN: This population-based registry study examined infants born in Texas between 1999 and 2014. Epidemiologic data relevant to fetal development were compared between cases of biliary atresia identified in the Texas Birth Defects Registry (n = 305) vs all live births (n = 4 689 920), and Poisson regression was used to calculate prevalence ratios (PRs) and 95% CIs. RESULTS: The prevalence of biliary atresia over the study period was 0.65 per 10 000 live births. Biliary atresia was positively associated with female sex (adjusted PR, 1.68; 95% CI, 1.33-2.12), delivery before 32-37 weeks of gestation (adjusted PR, 1.64; 95% CI, 1.18-2.29), delivery before 32 weeks of gestation (adjusted PR, 3.85; 95% CI, 2.38-6.22), and non-Hispanic Black vs non-Hispanic White maternal race/ethnicity (adjusted PR, 1.54, 95% CI, 1.06-2.24), while biliary atresia was inversely associated with season of conception in the fall relative to spring (adjusted PR, 0.62; 95% CI, 0.45-0.86). In addition, biliary atresia was associated with maternal diabetes (adjusted PR, 2.34; 95% CI, 1.57-3.48), with a stronger association with pregestational diabetes compared with gestational diabetes. In subgroup analyses, these associations were present in isolated biliary atresia cases that do not have any additional birth defects. CONCLUSIONS: Biliary atresia is associated with multiple factors related to fetal development, including pregestational maternal diabetes, female sex, and preterm birth. These associations also were observed in isolated cases of biliary atresia without other malformations or laterality defects. Our results are consistent with early life events influencing the pathogenesis of biliary atresia, and support further studies investigating in utero events to better understand etiology and time of onset.
Subject(s)
Biliary Atresia , Diabetes, Gestational , Premature Birth , Biliary Atresia/epidemiology , Female , Humans , Infant , Infant, Newborn , Live Birth , Pregnancy , PrevalenceABSTRACT
BACKGROUND/PURPOSE: There is a distinct lack of published studies evaluating the reasons for delay in definitive treatment of open fractures. This study aimed to determine the specific factors causing delay in the timely treatment of open fractures from the time of injury and to analyse the quality of treatment performed at the pre-hospital level. METHODS: In total, 250 consecutive patients with open fractures were assessed for time to surgery from injury and admission. The referred patients were analysed for distance of travel, level of referring hospital and appropriateness of care. The reasons for delay in terms of infrastructural- and patient-related factors were analysed individually and in combination. RESULTS: There were 37 direct patients (Group A) and 213 referred patients (Group B). Inappropriate care was present in 172 out of 213 (80.8%) referred patients. In total, 84% patients travelled more than 50 kms. The definitive surgery in referred patients was likely to be significantly delayed with regard to time from injury (29.84 vs 44.84 h, p ≤ 0.02). After admission, the time to surgery was greater than 24 h in 102 patients. Multivariate regression analysis determined that associated injuries and lack of fitness for surgery caused greater delay than non-availability of operation theatre or intensive care unit bed. CONCLUSION: Delayed referral, inadequate pre-hospital care and delay in surgery due to patient- and infrastructural-related issues at tertiary centre were identified as critical gaps in open fracture care in India. The importance of appropriate basic knowledge about management of open fractures should be emphasized at all structural level of care.
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With the rapidly increasing numbers of children diagnosed with obesity, pediatricians are facing more and more challenges regarding the complex care of these patients. Pediatric nonalcoholic fatty liver disease (NAFLD) is now the most prevalent cause of pediatric chronic liver disease, given its association with obesity. As NAFLD increases a child's risk of developing long-term complications including cirrhosis and hepatocellular carcinoma, efficient diagnosis and effective management is paramount. This article aims to provide a brief overview of NALFD, and discuss the updated diagnosis and management approach for pediatric NAFLD, with a particular focus on the role of the pediatrician. [Pediatr Ann. 2021;50(11):e474-e477.].
Subject(s)
Non-alcoholic Fatty Liver Disease/epidemiology , Pediatric Obesity/epidemiology , Carcinoma, Hepatocellular , Child , Humans , Liver Cirrhosis , Liver Neoplasms , Non-alcoholic Fatty Liver Disease/diagnosis , Non-alcoholic Fatty Liver Disease/therapy , Pediatric Obesity/complications , Pediatric Obesity/diagnosisABSTRACT
BACKGROUND: Rhino-orbito-cerebral mucormycosis(ROCM) is an uncommon yet potentially fatal fungal infection predominantly seen in immunocompromised individuals. However, there is very limited data available from India regarding outcome of patients with ROCM and diabetes mellitus. OBJECTIVE: To ascertain clinical parameters and factors in the final outcome of patients with diabetes mellitus and ROCM. MATERIALS AND METHODS: This series included retrospective analysis of medical records of 91 patients with diabetes mellitus who were diagnosed with ROCM from january 2007 to june 2019 at a tertiary care hospital in Punjab. RESULTS: The mean age of patients was 52.6 years (range 18-82 years), with men constituting the majority (71.4 %). Ophthalmoplegia was the most frequent presenting feature seen in 77 % of patients followed by proptosis (71 %). Intracranial involvement was seen in 20 % of the patients and cavernous sinus thrombosis was diagnosed in 9(10 %) patients. Out of 91 patients, 81 patients were subjected to appropriate surgical procedure depending upon site and extent of involvement by mucorales. A total of 53 (58.2 %) patients survived while 38(41.8 %) patients succumbed. Delay in presentation to hospital, intracranial extension and loss of vision at presentation adversely affected the outcome (p < 0.05). Aggressive surgical management in the form of multiple debridements was superior to single debridement (p < 0.05). Diabetic ketoacidosis did not significantly affect the outcome (p = 0.359). CONCLUSIONS: ROCM in patients with diabetes mellitus, is a rapidly progressive disease with a high fatality rate and grave outcome unless diagnosed early and managed aggressively.
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Acute pancreatitis as an initial manifestation of primary hyperparathyroidism (PHPT) is a rare occurrence and timely diagnosis of PHPT is crucial in preventing repeat attack of pancreatitis. The study aimed at evaluating the clinico-radiological profile of patients admitted with acute pancreatitis as the index presentation of PHPT and to determine the factors associated with development of severe pancreatitis. This series included retrospective analysis of medical records of 30 patients admitted with acute pancreatitis as initial manifestation of PHPT. Additionally, we analyzed the data of another 30 patients admitted with PHPT but without any evidence of pancreatitis, to serve as control group. The mean age of the subjects was 44.9±13.9 years with male to female ratio of 1.30. The mean serum calcium level was 12.24±2.79 mg/dl and five (16.6%) patients had normocalcemia at time of presentation. Presence of nephrolithiasis was significantly associated with severe pancreatitis. One patient had refractory hypercalcemia associated with renal failure and was successfully managed with denosumab. Patients with PHPT associated with acute pancreatitis had significantly higher calcium levels and lower frequency of skeletal involvement as compared to PHPT patients without pancreatitis. PHPT masquerading as acute pancreatitis is rare and high index of suspicion is required to diagnose this condition especially in the presence of normocalcemia at presentation. Patients with PHPT associated pancreatitis had male preponderance, higher calcium levels, and lower frequency of skeletal involvement as compared to PHPT patients without pancreatitis.
Subject(s)
Biomarkers/analysis , Hyperparathyroidism, Primary/diagnosis , Pancreatitis/diagnosis , Adult , Diagnosis, Differential , Female , Follow-Up Studies , Humans , Hyperparathyroidism, Primary/complications , Hyperparathyroidism, Primary/epidemiology , India/epidemiology , Male , Middle Aged , Pancreatitis/complications , Pancreatitis/epidemiology , Prognosis , Retrospective StudiesABSTRACT
Biallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic-intestinal and retinal-disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.
Subject(s)
Eye Diseases, Hereditary/genetics , Intestinal Mucosa/metabolism , Malabsorption Syndromes/genetics , Microvilli/pathology , Mucolipidoses/genetics , Polymorphism, Single Nucleotide , Qa-SNARE Proteins/genetics , Retinal Cone Photoreceptor Cells/metabolism , Retinal Dystrophies/genetics , Aged , Aged, 80 and over , Alcohol Oxidoreductases/genetics , Alcohol Oxidoreductases/metabolism , Animals , Autopsy , Co-Repressor Proteins/genetics , Co-Repressor Proteins/metabolism , Eye Diseases, Hereditary/metabolism , Eye Diseases, Hereditary/pathology , Female , Gene Expression Regulation , Homozygote , Humans , Intestinal Mucosa/pathology , Malabsorption Syndromes/metabolism , Malabsorption Syndromes/pathology , Mice , Mice, Knockout , Microvilli/genetics , Microvilli/metabolism , Mucolipidoses/metabolism , Mucolipidoses/pathology , Phenotype , Qa-SNARE Proteins/deficiency , RNA, Messenger/genetics , RNA, Messenger/metabolism , Retinal Cone Photoreceptor Cells/pathology , Retinal Dystrophies/metabolism , Retinal Dystrophies/pathology , Sensory Rhodopsins/genetics , Sensory Rhodopsins/metabolism , Exome SequencingABSTRACT
BACKGROUND AND AIMS: Diabetes Mellitus (DM) is a modifiable and independent risk factor for stroke. As the clinical features, radiological profile, outcome and prognosis of the stroke in type 2 diabetic and non diabetic patients are significantly variable, we proposed to evaluate these variations of stroke in patients with or without Type 2 DM. MATERIAL AND METHODS: A prospective study was conducted from January, 2011 to June, 2012 on in-hospital admitted diabetic and non diabetic patients presenting with stroke. Data was recorded on a predesigned Performa. RESULTS: A total of 150 cases were enrolled into the study. Out of these, 66% of patients had ischemic stroke and 34% of patients had hemorrhagic stroke. Type 2 diabetes mellitus was present in 52% patients. Ischemic stroke was significantly higher in diabetics than non diabetics (P = 0.007); however, hemorrhagic stroke was more in non diabetics. Mean age was significantly higher in diabetics (P = 0.04). CAD (P = 0.04), recurrent stroke (P = 0.006) had significant association with diabetes. Large vessel stroke was more common than small vessel stroke. Anterior circulation stroke was more common than posterior circulation stroke. There was significant improvement in morbidity and disability of the patients on follow up with treatment. CONCLUSIONS: A greater incidence of anterior circulation ischemic stroke, and recurrent strokes occur in patients with DM.
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Liver biopsy is the cornerstone of medical decision-making for a wide range of hepatic diseases in children. The indications for liver biopsy vary greatly depending on the ease of diagnosis with non-invasive tests, the need to stage of disease, and the role of histological evaluation in management of liver disease. Multiple methods of liver biopsy are available to the clinician and are utilized based on clinical circumstances, cost, and consideration of contraindications. Collaboration between the clinician and pathologist is important in order to handle the tissue sample appropriately and interpret the histology. The purpose of this paper is to provide a broad overview of liver biopsy indications, techniques, pre- and post-biopsy care and complications, interpretations, contraindications, recent advancements, and pitfalls that occur with liver biopsies.
Subject(s)
Liver Diseases , Liver , Biopsy , Child , Contraindications , Humans , Liver Diseases/diagnosisABSTRACT
Parenteral Nutrition (PN) Associated Liver Disease (PNALD) affects up to 60% of neonates; however, techniques for diagnosing and monitoring disease progression remain limited. The neonatal baboon model may provide a unique opportunity to identify serologic markers associated with this disease. The purpose of this study was to investigate if Hyaluronic Acid (HA), TIMP metallopeptidase inhibitor 1 (TIMP1), Amino-terminal Propeptide of Type-III Collagen (PIIINP) and Enhanced Liver Fibrosis (ELF) score associate with histological liver disease in neonatal baboons exposed to PN. Preterm baboons delivered via c-section at 67% gestation received PN for 14 days with or without Intralipid (PRT+IL, PRT-IL, respectively) or were sacrificed after birth (PRTCTR). Term baboons were sacrificed after birth (TERMCTR) or survived 14 days (TERM+14d). Serum HA, TIMP1, and PIIINP concentrations were measured by ELISA. A blinded pathologist assigned liver histological scores following necropsy. HA increased 9.1-fold, TIMP1 increased 2.2-fold, and ELF score increased 1.4-fold in PRT-IL compared to PRTCTR. ALT, AST, and GGT were within normal limits and did not vary between groups. A trend towards increased fibrosis was found in PRT-IL baboons. Microvesicular hepatocyte steatosis and Kupffer cell hypertrophy were elevated in PRT-IL vs PRTCTR. HA and TIMP1 were significantly elevated in preterm baboons with early histological findings of liver disease evidenced by hepatic steatosis, Kupffer cell hypertrophy and a trend towards fibrosis whereas traditional markers of liver disease remained normal. These novel markers could potentially be utilized for monitoring early hepatic injury in neonates.
Subject(s)
Biomarkers/blood , Liver Diseases/metabolism , Parenteral Nutrition/adverse effects , Primate Diseases/metabolism , Animals , Animals, Newborn , Disease Models, Animal , Female , Hyaluronic Acid/blood , Kupffer Cells/pathology , Liver Diseases/etiology , Liver Diseases/pathology , Male , Papio , Premature Birth , Primate Diseases/chemically induced , Primate Diseases/pathology , Tissue Inhibitor of Metalloproteinase-1/bloodABSTRACT
For children under 12 years of age who have chronic hepatitis C virus (HCV) infection, there are currently no approved treatments with direct-acting antiviral agents. We therefore evaluated the safety and efficacy of ledipasvir-sofosbuvir in HCV-infected children aged 3 to <6 years. In an open-label study, patients 3 to <6 years old chronically infected with HCV genotype 1 (n = 33) or 4 (n = 1) received weight-based doses of combined ledipasvir-sofosbuvir as granules (33.75 mg/150 mg for weights <17 kg or 45 mg/200 mg for weights ≥17 kg) for 12 weeks. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12). For the first 14 patients, intensive pharmacokinetic sampling was done on day 10 of treatment. All patients had been infected through perinatal transmission and were treatment naïve. No patients had known cirrhosis. Ten patients (29%) weighed <17 kg. SVR12 was achieved in 97% of patients (33 of 34); the patient who did not achieve SVR12 was 3 years old and discontinued treatment after 5 days because of an adverse event "abnormal drug taste." The most common adverse events were vomiting (24% of patients), cough (21%), and pyrexia (21%). No patients experienced a serious adverse event. Intensive pharmacokinetic analysis of 13 patients for whom data were evaluable confirmed that the doses selected were appropriate. Conclusion: Ledipasvir-sofosbuvir was well tolerated and highly effective in children 3 to <6 years old with chronic HCV infection.