Hematospermia and Cloacogenic Transitional Cell Carcinoma: A Twist on Significance and Meaning

A 52-year-old gentleman presented with recurrent hematospermia. Further history revealed recent onset of constipation and difficulty voiding. Rectal examination revealed a firm, polypoid mass and colonoscopy showed suspicious, ulcerated lesions of the rectal mucosa with narrowing of the rectal vault. Pathology demonstrated transitional cell carcinoma of the rectum. While transitional cell carcinoma is a common genitourinary cancer, its presence in the anus and rectum is exceedingly rare. Furthermore, hematospermia is generally not associated with malignancy. This case is a remarkable example of two pathologic processes presenting in rare form and underscores the value of a thorough investigation of hematospermia when associated with other clinical symptoms

Neonatal Enteropathogenic Escherichia coli Infection Disrupts Microbiota-Gut-Brain Axis Signaling

Diarrheal diseases are a leading cause of death in children under the age of 5 years worldwide. Repeated early-life exposures to diarrheal pathogens can result in comorbidities including stunted growth and cognitive deficits, suggesting an impairment in the microbiota-gut-brain (MGB) axis. Neonatal C57BL/6 mice were infected with enteropathogenic Escherichia coli (EPEC) (strain e2348/69; ΔescV [type III secretion system {T3SS} mutant]) or the vehicle (Luria-Bertani [LB] broth) via orogastric gavage at postnatal day 7 (P7). Behavior (novel-object recognition [NOR] task, light/dark [L/D] box, and open-field test [OFT]), intestinal physiology (Ussing chambers), and the gut microbiota (16S Illumina sequencing) were assessed in adulthood (6 to 8 weeks of age). Neonatal infection of mice with EPEC, but not the T3SS mutant, caused ileal inflammation in neonates and impaired recognition memory (NOR task) in adulthood. Cognitive impairments were coupled with increased neurogenesis (Ki67 and doublecortin immunostaining) and neuroinflammation (increased microglia activation [Iba1]) in adulthood. Intestinal pathophysiology in adult mice was characterized by increased secretory state (short-circuit current [Isc]) and permeability (conductance) (fluorescein isothiocyanate [FITC]-dextran flux) in the ileum and colon of neonatally EPEC-infected mice, along with increased expression of proinflammatory cytokines (Tnfα, Il12, and Il6) and pattern recognition receptors (Nod1/2 and Tlr2/4). Finally, neonatal EPEC infection caused significant dysbiosis of the gut microbiota, including decreased Firmicutes, in adulthood. Together, these findings demonstrate that infection in early life can significantly impair the MGB axis in adulthood

Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding–deficient channels

The Ca2+-binding protein calmodulin has emerged as a pivotal player in tuning Na+ channel function, although its impact in vivo remains to be resolved. Here, we identify the role of calmodulin and the NaV1.5 interactome in regulating late Na+ current in cardiomyocytes. We created transgenic mice with cardiac-specific expression of human NaV1.5 channels with alanine substitutions for the IQ motif (IQ/AA). The mutations rendered the channels incapable of binding calmodulin to the C-terminus. The IQ/AA transgenic mice exhibited normal ventricular repolarization without arrhythmias and an absence of increased late Na+ current. In comparison, transgenic mice expressing a lidocaine-resistant (F1759A) human NaV1.5 demonstrated increased late Na+ current and prolonged repolarization in cardiomyocytes, with spontaneous arrhythmias. To determine regulatory factors that prevent late Na+ current for the IQ/AA mutant channel, we considered fibroblast growth factor homologous factors (FHFs), which are within the NaV1.5 proteomic subdomain shown by proximity labeling in transgenic mice expressing NaV1.5 conjugated to ascorbate peroxidase. We found that FGF13 diminished late current of the IQ/AA but not F1759A mutant cardiomyocytes, suggesting that endogenous FHFs may serve to prevent late Na+ current in mouse cardiomyocytes. Leveraging endogenous mechanisms may furnish an alternative avenue for developing novel pharmacology that selectively blunts late Na+ current

A <i>CACNA1C</i> Variant Associated with Reduced Voltage-Dependent Inactivation, Increased Ca_V1.2 Channel Window Current, and Arrhythmogenesis

<div><p>Mutations in <i>CACNA1C</i> that increase current through the Ca_V1.2 L-type Ca²⁺ channel underlie rare forms of long QT syndrome (LQTS), and Timothy syndrome (TS). We identified a variant in <i>CACNA1C</i> in a male child of Filipino descent with arrhythmias and extracardiac features by candidate gene sequencing and performed functional expression studies to electrophysiologically characterize the effects of the variant on Ca_V1.2 channels. As a baby, the subject developed seizures and displayed developmental delays at 30 months of age. At age 5 years, he displayed a QTc of 520 ms and experienced recurrent VT. Physical exam at 17 years of age was notable for microcephaly, short stature, lower extremity weakness and atrophy with hyperreflexia, spastic diplegia, multiple dental caries and episodes of rhabdomyolysis. Candidate gene sequencing identified a G>C transversion at position 5731 of <i>CACNA1C</i> (rs374528680) predicting a glycine>arginine substitution at residue 1911 (p.G1911R) of Ca_V1.2. The allele frequency of this variant is 0.01 in Malays, but absent in 984 Caucasian alleles and in the 1000 genomes project. In electrophysiological analyses, the variant decreased voltage-dependent inactivation, thus causing a gain of function of Ca_V1.2. We also observed a negative shift of V_1/2 of activation and positive shift of V_1/2 of channel inactivation, resulting in an increase of the window current. Together, these suggest a gain-of-function effect on Ca_V1.2 and suggest increased susceptibility for arrhythmias in certain clinical settings. The p.G1911R variant was also identified in a case of sudden unexplained infant death (SUID), for which an increasing number of clinical observations have demonstrated can be associated with arrhythmogenic mutations in cardiac ion channels. In summary, the combined effects of the <i>CACNA1C</i> variant to diminish voltage-dependent inactivation of Ca_V1.2 and increase window current expand our appreciation of mechanisms by which a gain of function of Ca_V1.2 can contribute to QT prolongation.</p></div

Electrophysiological parameters for the wild type and p.G1911R mutant channel.

<p>Numbers tested are in parentheses.</p><p>*p<0.05 vs WT.</p><p>Electrophysiological parameters for the wild type and p.G1911R mutant channel.</p

Location of the p.G1911R variant in the α_1C subunit of Ca_V1.2.

<p>A: Schematic of the Ca_V1.2 channel pore-forming α_1C subunit and the auxiliary α₂δ and β subunit. The p.G1911R variant is in the C-terminus close to the calcineurin (CaN) binding site. The location of other mutations in α_1C previously associated with TS are also indicated, including the most commonly reported p.G402R and p.G406R in the loop between DI and DII, and A1473G in the transmembrane segment 6 in the DIV. AID, α1 subunit interacting domain. B: Sanger sequencing of a normal control (WT) and the patient’s DNA showing the p.G1911R variant (arrow). C: Amino acid alignment shows conservation among species of glycine (G) at position 1911 also showing the CaN binding domain.</p