Simultaneous Bilateral Tibial Tuberosity Avulsions—Over 6-Year Follow-up

Abstract Simultaneous bilateral avulsions of the tibial tuberosity are rare injuries. The authors found only five reported cases in the orthopedic literature. We add a further case of bilateral avulsions of the tibial tuberosity with the longest reported follow-up.     

Synthesis and biological evaluation of prodrugs of zidovudine

A series of prodrugs of zidovudine (AZT) has been synthesized in an effort to enhance the uptake of the prodrugs by the HIV-1 infected cells and to increase the plasma half-life of AZT. The 5'-OH function of AZT was esterified with various acids in the presence of DCC and 4-(dimethylamino)pyridine (DMAP). The prodrug moieties included (a) morpholine and N-phenylpiperazine-1-acetic acid, (b) 1,4-dihydro-1-methyl-3-nicotinic acid, (c) retinoic acid, and (d) certain amino acids. The anti-HIV-1 activity of the esters was determined in peripheral blood lymphocytes. The IC50 for AZT in this system was 0.12 microM whereas for prodrugs it ranged from 0.05 to 0.2 microM. The prodrugs were generally less cytotoxic than AZT except the retinoic acid ester. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterases with t1/2 ranging from 10 to 240 min. Drug uptake studies in H9 cells with radiolabeled analogues demonstrated that the retinoic acid ester achieved approximately 4-fold higher intracellular concentration than [3H]AZT. However, 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester (5) was the most active agent of this series and had a higher therapeutic index than AZT.     

Genomic diagnostics in polycystic kidney disease: an assessment of real-world use of whole-genome sequencing

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is common, with a prevalence of 1/1000 and predominantly caused by disease-causing variants in PKD1 or PKD2. Clinical diagnosis is usually by age-dependent imaging criteria, which is challenging in patients with atypical clinical features, without family history, or younger age. However, there is increasing need for definitive diagnosis of ADPKD with new treatments available. Sequencing is complicated by six pseudogenes that share 97% homology to PKD1 and by recently identified phenocopy genes. Whole-genome sequencing can definitively diagnose ADPKD, but requires validation for clinical use. We initially performed a validation study, in which 42 ADPKD patients underwent sequencing of PKD1 and PKD2 by both whole-genome and Sanger sequencing, using a blinded, cross-over method. Whole-genome sequencing identified all PKD1 and PKD2 germline pathogenic variants in the validation study (sensitivity and specificity 100%). Two mosaic variants outside pipeline thresholds were not detected. We then examined the first 144 samples referred to a clinically-accredited diagnostic laboratory for clinical whole-genome sequencing, with targeted-analysis to a polycystic kidney disease gene-panel. In this unselected, diagnostic cohort (71 males :73 females), the diagnostic rate was 70%, including a diagnostic rate of 81% in patients with typical ADPKD (98% with PKD1/PKD2 variants) and 60% in those with atypical features (56% PKD1/PKD2; 44% PKHD1/HNF1B/GANAB/ DNAJB11/PRKCSH/TSC2). Most patients with atypical disease did not have clinical features that predicted likelihood of a genetic diagnosis. These results suggest clinicians should consider diagnostic genomics as part of their assessment in polycystic kidney disease, particularly in atypical disease.Subject terms: Genetics research, Polycystic kidney disease, Genetic testing     

Acitretin‐Responsive Ichthyosis in Chanarin–Dorfman Syndrome with a Novel Mutation in the ABHD5/CGI‐58 Gene

Chanarin–Dorfman syndrome (CDS) is a rare nonlysosomal neutral lipid storage disorder characterized by congenital ichthyosis, lipid vacuoles in leukocytes (Jordan's anomaly), and hepatomegaly. The authors herein report an 18‐month‐old boy with ichthyosis and hepatomegaly diagnosed with CDS and confirmed to have a novel c.506–3C>G mutation in the ABHD5/CGI‐58 gene. Our case also illustrates that retinoids such as acitretin could be useful in the treatment of skin manifestations in CDS even in the presence of liver derangement.     

Conjunctival Melanoma in Asian Indians: A Study of 42 Patients

Purpose: To describe the clinical features, treatment, and outcomes of conjunctival melanoma in Asian Indians.

Methods: Retrospective study of 42 patients.

Results: The mean age at presentation of conjunctival melanoma was 43 years (median, 45 years; range, 9–78 years). There were 20 (48%) males and 22 (52%) females. Nineteen patients (45%) had a known history of a preexisting pigmented conjunctival lesion. Bulbar conjunctiva (n = 28; 67%) was the most common tumor epicenter, and medial ocular surface quadrant (n = 15; 36%) was more commonly involved. The mean tumor basal diameter was 12 mm (median, 10 mm; range, 4–30 mm), and the mean tumor thickness was 4 mm (median, 2 mm; range, 1–30 mm). Majority of the patients had a pigmented tumor (n = 33; 79%). The tumors arose de novo (n = 17, 41%) or were associated with conjunctival nevus (n = 9; 21%) or primary acquired melanosis (n = 16, 38%). Wide excisional biopsy, adjunctive cryotherapy, and amniotic membrane grafting were performed in 27 (71%) patients, 11 (29%) underwent orbital exenteration, and 4 were lost to follow-up prior to definitive treatment. Over a mean follow-up period of 24 months (median, 9 months; range, <1 to 136 months), four (11%) patients had tumor recurrence, seven (18%) had locoregional lymph node metastasis, and four (11%) developed systemic metastasis and died due to metastatic disease.

Conclusion: Conjunctival melanoma predominantly occurs in middle-aged Asian Indians and is associated with a high rate of systemic metastasis and death.     

Can neuroimaging help aphasia researchers? Addressing generalizability,variability, and interpretability

Neuroimaging studies of individuals with brain damage seek to link brain structure and activity to cognitive impairments, spontaneous recovery, or treatment outcomes. To date, such studies have relied on the critical assumption that a given anatomical landmark corresponds to the same functional unit(s) across individuals. However, this assumption is fallacious even across neurologically healthy individuals. Here, we discuss the severe implications of this issue, and argue for an approach that circumvents it, whereby: (i) functional brain regions are defined separately for each subject using fMRI, allowing for inter-individual variability in their precise location; (ii) the response profile of these subject-specific regions are characterized using various other tasks; and (iii) the results are averaged across individuals, guaranteeing generalizabliity. This method harnesses the complementary strengths of single-case studies and group studies, and it eliminates the need for post hoc “reverse inference” from anatomical landmarks back to cognitive operations, thus improving data interpretability.