Blood Constituents, Antioxidant Activities and Hormonal Profile in She-camels (Camelus dormedarius) during different Physiological Statuses in the North Western Coast of Egypt

To monitor blood constituents and hormonal profiles in dromedary she-camels at different physiological statuses in the Northwestern Coast of Egypt, twenty-four she-camels, aged 7-10 years were used from December 2016 to March 2019. Animals were divided according estrous behavior and ultrasound scans of ovarian structures into estrus and non-estrus groups before natural mating. Pregnancy was diagnosed 30 days after mating by ultrasonography. Blood samples were collected from all animals during estrus and non-estrus and monthly during gestation and lactation periods. During the follicular phase GLC and P4 levels decreased (P<0.05). Levels of E2 and PRL increased (P<0.05). Follicles number and diameter in both ovaries increased (P<0.05) in estrus group. Cyclic status correlated negatively with GLC, P4, total number follicles of left ovary (TLO) and diameter follicles of left ovary (DLO) and positively with AST, E2 and DLO. In 1st trimester of pregnancy, GLC levels decreased. Higher (P<0.05) activity of ALT (2nd and 3rd trimesters) and ALP (1st and 2nd trimesters) were recorded. SOD and HP changed (P<0.05). Pregnancy status correlated negatively with GLC, ALP, HP and SOD and positively with TG and ALT. During lactation, ALB, CHOL, TG, ALT, ALP, P4 and PRL were affected (P<0.05). SOD and HP were higher (P<0.05) in 2nd and 1st trimester, respectively. Lactation status correlated negatively with P4 and PRL and positively with CHOL, ALB, ALP, ALT and TAC. In conclusion, the knowledge the values of hormonal, blood biochemical, antioxidant activities are necessary for diagnostic interpretation of pathological and adjusting the different functions throughout different physiological statuses under arid conditions.

Diffuse PRAME Expression Is Highly Specific for Thin Melanomas in the Distinction from Severely Dysplastic Nevi but Does Not Distinguish Metastasizing from Non-Metastasizing Thin Melanomas

Background: PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemistry is increasingly used as diagnostic adjunct in the evaluation of melanocytic tumors. The expression and prognostic significance of PRAME in melanomas ≤1.0 mm and its diagnostic utility in the distinction from severely dysplastic compound nevi (SDN) have not been studied. Methods: We investigated and compared the immunohistochemical PRAME expression in 70 matched thin metastasizing and non-metastasizing melanomas and 45 nevi from patients with long-term follow-up (35 SDN and 10 unequivocally benign compound nevi). Results: Diffuse PRAME staining in >75% of lesional epidermal and dermal melanocytes identified 58.6% of thin melanomas but did not distinguish metastasizing from non-metastasizing melanomas (p = 0.81). A superficial atypical melanocytic proliferation of uncertain significance, in which the final diagnostic interpretation favored a SDN was the only nevus with diffuse PRAME expression (1/45). Melanomas and SDN with PRAME immunoreactivity exhibited different staining patterns. Most melanomas (67.6%) showed uniform PRAME expression in the in situ and invasive component, whereas most SDN (81.0%) showed a decreasing gradient with depth. Conclusion: Diffuse intraepidermal and dermal PRAME staining is highly specific for melanomas in the distinction from SDN. PRAME expression is not a prognostic biomarker in melanomas ≤1.0 mm.

Mitochondrial DNA variation across 56,434 individuals in gnomAD

Databases of allele frequency are extremely helpful for evaluating clinical variants of unknown significance; however, until now, genetic databases such as the Genome Aggregation Database (gnomAD) have ignored the mitochondrial genome (mtDNA). Here we present a pipeline to call mtDNA variants that addresses three technical challenges: (i) detecting homoplasmic and heteroplasmic variants, present respectively in all or a fraction of mtDNA molecules, (ii) circular mtDNA genome, and (iii) misalignment of nuclear sequences of mitochondrial origin (NUMTs). We observed that mtDNA copy number per cell varied across gnomAD cohorts and influenced the fraction of NUMT-derived false-positive variant calls, which can account for the majority of putative heteroplasmies. To avoid false positives, we excluded samples prone to NUMT misalignment (few mtDNA copies per cell), cell line artifacts (many mtDNA copies per cell), or with contamination and we reported variants with heteroplasmy greater than 10%. We applied this pipeline to 56,434 whole genome sequences in the gnomAD v3.1 database that includes individuals of European (58%), African (25%), Latino (10%), and Asian (5%) ancestry. Our gnomAD v3.1 release contains population frequencies for 10,850 unique mtDNA variants at more than half of all mtDNA bases. Importantly, we report frequencies within each nuclear ancestral population and mitochondrial haplogroup. Homoplasmic variants account for most variant calls (98%) and unique variants (85%). We observed that 1/250 individuals carry a pathogenic mtDNA variant with heteroplasmy above 10%. These mitochondrial population allele frequencies are publicly available at gnomad.broadinstitute.org and will aid in diagnostic interpretation and research studies.

A brief history of diabetes genetics: insights for pancreatic beta-cell development and function

Since the discovery of insulin 100 years ago, our knowledge and understanding of diabetes has grown exponentially. Specifically, with regards to the genetics underlying diabetes risk, our discoveries have paralleled developments in our understanding of the human genome and our ability to study genomics at scale; these advancements in genetics have both accompanied and led to those in diabetes treatment. This review will explore the timeline and history of gene discovery and how this has coincided with progress in the fields of genomics. Examples of genetic causes of monogenic diabetes are presented and the continuing expansion of allelic series in these genes and the challenges these now cause for diagnostic interpretation along with opportunities for patient stratification are discussed.

The Great Mime: Three Cases of Melanoma with Carcinoid-Like and Paraganglioma-Like Pattern with Emphasis on Differential Diagnosis

Melanoma is among the most aggressive tumors, with different histological patterns of presentation ranging from the usual and easily diagnosable pictures to complex patterns of difficult diagnostic interpretation. Here, we present three cases of a very rare melanoma variant described as “carcinoid-like” and “paraganglioma-like” in the literature, and a brief review of the current literature of the very few cases described to date.

A CADAVERIC STUDY OF VARIATIONS IN THE ANATOMY OF BRACHIAL ARTERY AND ITS BRANCHING PATTERS

Background: Knowledge of the normal and variant arterial anatomy of the upper extremity is of signicant clinical importance for the vascular radiologist and surgeons for accurate diagnostic interpretation as well as in the conduct of interventional and surgical procedures on the upper extremity. The anatomical knowledge of the anomalous branching pattern of the brachial artery is important during percutaneous arterial catheterization, so as to prevent any complications arising from accidental damage to the anomalous vessel and knowledge of the variations are important for plastic surgeons using aps for reconstructive surgeries. Methods: The present study was undertaken on 50 upper limbs of both sexes from embalmed adult human cadaver in department of Anatomy, Patna Medical College, Patna, Bihar. Results: In the present study, normal brachial artery was found in 42 specimens accounting for 84%. Variations were found in 8 specimens (16%); of these ve specimens presented with trifurcation of brachial artery into radial, ulnar and radial recurrent arteries (10%); one specimen presented with double profunda brachii artery (2%); one specimen showed high origin of radial artery (2%) and one specimen presented with high division of brachial artery in the proximal third of arm (2%). Conclusions: Accurate anatomical knowledge about the brachial artery and its branching pattern with their variations are important for physicians, cardiologists, vascular surgeons and interventional radiologists. Study of these variations and its awareness helps in avoiding the iatrogenic injuries of the blood vessels, in the management of accidental/traumatic injuries to arteries in upper limb and during diagnostic procedures (like arteriograms).

Diagnostic Interpretation of Non-Uniformly Sampled Electrocardiogram

We present a set of three fundamental methods for electrocardiogram (ECG) diagnostic interpretation adapted to process non-uniformly sampled signal. The growing volume of ECGs recorded daily all over the world (roughly estimated to be 600 TB) and the expectance of long persistence of these data (on the order of 40 years) motivated us to challenge the feasibility of medical-grade diagnostics directly based on arbitrary non-uniform (i.e., storage-efficient) ECG representation. We used a refined time-independent QRS detection method based on a moving shape matching technique. We applied a graph data representation to quantify the similarity of asynchronously sampled heartbeats. Finally, we applied a correlation-based non-uniform to time-scale transform to get a multiresolution ECG representation on a regular dyadic grid and to find precise P, QRS and T wave delimitation points. The whole processing chain was implemented and tested with MIT-BIH Database (probably the most referenced cardiac database) and CSE Multilead Database (used for conformance testing of medical instruments) signals arbitrarily sampled accordingly to a perceptual model (set for variable sampling frequency of 100–500 Hz, compression ratio 3.1). The QRS detection shows an accuracy of 99.93% with false detection ratio of only 0.18%. The classification shows an accuracy of 99.27% for 14 most frequent MIT-BIH beat types and 99.37% according to AAMI beat labels. The wave delineation shows cumulative (i.e., sampling model and non-uniform processing) errors of: 9.7 ms for P wave duration, 3.4 ms for QRS, 6.7 ms for P-Q segment and 17.7 ms for Q-T segment, all the values being acceptable for medical-grade interpretive software.

Amino Acid-level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally-identified TTN -Encoded Titin Truncating Variants

Background - TTN , the largest gene in the human body, encodes titin (TTN), a protein that plays key structural, developmental, and regulatory roles in skeletal and cardiac muscle. Variants in TTN , particularly truncating variants (TTNtvs), have been implicated in the pathogenicity of cardiomyopathy (CM). Despite this link, there is also a high burden of TTNtvs in the ostensibly healthy general population. This complicates the diagnostic interpretation of incidentally identified TTNtvs which are of increasing abundance given expanding clinical exome sequencing (ES). Methods - Incidentally identified TTNtvs were obtained from a large referral database of clinical ES (Baylor Genetics) and compared to rare population variants from gnomAD and CM-associated variants from cohort studies in the literature. A subset of TTNtv-positive children evaluated for cardiomyopathy at Texas Children's Hospital (TCH) were retrospectively reviewed for clinical features of cardiomyopathy. Amino acid-level signal-to-noise analysis (S:N) was performed. Results - Pathologic hotspots were identified within the A-band and N-terminal I-band that closely correlated with regions of high percent spliced in (PSI) of exons. Incidental TTNtvs and population TTNtvs did not localize to these regions. Variants were re-classified based on current ACMG criteria with incorporation of S:N analysis among TCH cases. Those re-classified as likely pathogenic or pathogenic were more likely to have evidence of CM on echocardiography than those re-classified as variants of unknown significance. Conclusions - Incidentally found TTNtvs are common among clinical ES referrals. Pathologic hotspots within the A-band of TTN may be informative in determining variant pathogenicity when incorporated into current ACMG guidelines.

Initial Evaluation of Rapid, Direct-to-Digital Prostate Biopsy Pathology

Context.— Pathologist interobserver discordance is significant in grading of prostate cancer, limiting reliability. Diagnostic reproducibility may be improved with digital images, but adoption faces workflow, cost, and quality challenges. A novel digital method using an alternative tissue processing approach and novel laser microscopy system potentially addresses these issues. Objective.— To evaluate the capability of this new method for primary diagnostic interpretation in clinical prostate biopsy specimens. Design.— Forty patients with a high likelihood of prostate cancer based on magnetic resonance imaging consented to investigational core biopsy. A subset of samples was used for direct comparison of physical slide preparation effects and time-tracking determination with multiphoton microscopy. Twenty samples were processed for diagnostic comparison between multilevel digital slides and subsequently produced physical slides. A reference diagnosis based on all data was established using grade groups. Level of diagnostic match and requests for immunohistochemistry were compared between physical and digital diagnoses. Immunohistochemical staining and length measurements were secondary outcomes. Results.— Interpretations based on direct multiphoton imaging yielded diagnoses that were at least as accurate as standard histology; cancer diagnosis correlation was 89% (51 of 57) by physical slides and 95% (53 of 56) by multiphoton microscopy. Grade-level concordance was 73% (44 of 60) by either method. Immunohistochemistry for routine prostate cancer–associated markers on these alternatively processed tissues was unaffected. Alternatively processed tissues resulted in longer measured core and cancer lengths, suggestive of improved orientation and visualization. Conclusions.— Findings support high potential for complete interpretation of prostate core biopsies using solely multiphoton microscopy of intact specimens, with potential diagnostic benefits as well as reduced processing time and reduced processing complexity.