Infective endocarditis infects the heart's inner surface, mostly the valves. It is a lethal disease with a high rate of morbidity and fatality. It mostly caused by bacteria, but fungi can also cause it. Microbiological diagnosis relies on blood culture. Molecular and biochemical indicators add to diagnosis, particularly in culture-negative patients. This study aimed to decide the role of 16s rRNA, procalcitonin, and high sensitivity C reactive protein (hsCRP) in the diagnosis of culture negative infective endocarditis (CNIE) in Assiut university hospitals. This cross-sectional study included 60 patients who were admitted to cardiac hospitals with suspected infective endocarditis according to modified DUKE criteria. A group of 20 apparently healthy subjects served as a control group for investigation of inflammatory biomarkers. We performed blood culture, biochemical markers and molecular investigations. Of the 60 patients, there were 46 (76.7%) culture positives and 14 (23.3%) culture negatives. Staphylococcus aureus was the most prevalent pathogen in culture positive patients, followed by enterococcus and klebsiella. Linezolid and imipenem were the most sensitive antibiotics for Gram-positive and Gram-negative bacteria, respectively. Amplification of bacterial 16S rRNA gene, after DNA extraction from whole blood samples, was positive in 11/14 cases (78.5%) of culture negative patients and in 42/46 cases (91.3%) of culture positive patients. The range of procalcitonin in culture positive patients was (0.32- 89) ng/ml, significantly higher than in culture negative patients (0.02- 8.8) ng/ml, and in the control group (0.01-0.08) ng/ml. hsCRP showed the same pattern. In conclusion, our data suggest that PCR was the most accurate diagnostic tool for diagnosing CNIE, followed by procalcitonin, and hsCRP, respectively.

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Here we report biallelic mutations in the sorbitol dehydrogenase gene (SORD) as the most frequent recessive form of hereditary neuropathy. We identified 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state. SORD is an enzyme that converts sorbitol into fructose in the two-step polyol pathway previously implicated in diabetic neuropathy. In patient-derived fibroblasts, we found a complete loss of SORD protein and increased intracellular sorbitol. Furthermore, the serum fasting sorbitol levels in patients were dramatically increased. In Drosophila, loss of SORD orthologs caused synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient-derived fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a novel and potentially treatable cause of neuropathy and may contribute to a better understanding of the pathophysiology of diabetes.