Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1‐related syndrome

Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra‐renal abnormalities. Using trio exome sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one‐day‐old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post‐zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10%) and sperm (20%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow‐up studies for presumed de novo and low‐level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations.     

Fine-needle aspiration of a metaplastic breast carcinoma with extensive melanocytic differentiation: a case report

Metaplastic carcinomas of the breast are uncommon breast tumors with aberrant cellular differentiation, most commonly showing ductal, squamous, and mesenchymal components. A breast carcinoma composed of both epithelial and melanocytic differentiation is rare, with only four previously reported cases in the literature. We present the fifth reported case, where the diagnosis was suggested by fine-needle aspiration (FNA) and later confirmed after the surgical specimen was excised. Histologically, this neoplasm revealed multidirectional differentiation, consisting primarily of squamous and melanocytic cell types, with focal glandular and osseous metaplasia. Based on the morphologic, immunohistochemical, and ultrastructural findings, we conclude that such tumors fall within the spectrum of metaplastic carcinomas of the breast. We believe that this case will further contribute to the understanding of this enigmatic tumor.     

On the elementary conductance event produced by L-glutamate and quanta of the natural transmitter at the neuromuscular junctions of Maia squinado.

1. The membrane potential of giant muscle fibres of Maia squinado was measured with an intracellular wire electrode. On applying L-glutamate to the fibre the cell deplorized and fluctuations of the membrane potential around its mean level--glutamate noise--were seen. 2. The variance of the glutamate voltage noise is proportional to the mean level of depolarization. The noise can be regarded as being caused by numerous exponentially decaying elementary voltage events about 5 X 10(-10) V in amplitude. The miniature excitatory junctional potential (min.e.j.p.) is approximately 6000 times the amplitude of the elementary voltage event produced by L-glutamate. 3. The power spectrum of glutamate voltage noise is a Lorentzian with a half-power frequency of approximately 20 Hz. 4. Min. e.j.p.s. decay exponentially with a time constant that coincides with the average lifetime of the elementary glutamate voltage event. 5. When glutamate is applied locally to a spot where extracellular min. e.j.p.s. can be recorded with a focal glass pipette, extracellular glutamate noise is seen. Glutamate noise could not be detected from elsewhere on the fibre. 6. The variance of the extracellular noise is proportional to the mean extracellular potential, and its power spectrum is a Lorentzian with a half-power frequency of about 110 Hz. 7. The extracellular min. e.j.p.s decay exponentially with a time constant that coincides with average lifetime of the elementary glutamate current event. 8. It is suggested that the decay of the quantal currents flowing at the excitatory junction is limited by the closure of the conductance channels in the post-synaptic membrane and not by the relaxation of the transmitter concentration in the synaptic cleft.     

Identification of the nuclear localization signal of human papillomavirus type 16 L1 protein.

Human papillomavirus type 16(HPV16) L1 and L2 capsid proteins can be detected only in the nucleus of infected cells. For other nuclear proteins, specific sequences of basic amino acids(aa) termed nuclear localization signals (NLS) direct the protein from the cytoplasm to the nucleus. We used a series of deletion and substitution mutations of the HPV16 L1 protein, produced by recombinant vaccinia virus (rVV), to identify NLS within HPV16 L1 and showed that HPV16 L1 contains two NLS sequences, each containing basic aa clusters. One NLS consisted of 6 basic amino acids (KRKKRK from aa 525 to 530) at the carboxy terminal end of L1. The other NLS contained 2 basic aa clusters(KRK from aa 510 to 512 and KR at aa 525, 526) separated by 12 amino acids. Mutations in either NLS did not alter nuclear localization of L1 when the other remained intact, but mutations to both prevented nuclear localization of L1. The L1 NLS could be overridden by introduction of a membrane binding sequence at the amino terminal end of the protein. A databases search showed that all sequenced papillomaviruses are predicted to have L1 and L2 capsid proteins with sequences of basic amino acids homologous with one or both NLS of HPV16 L1.     

Three-dimensional eye-head coordination during gaze saccades in the primate

The purpose of this investigation was to describe the neural constraints on three-dimensional (3-D) orientations of the eye in space (Es), head in space (Hs), and eye in head (Eh) during visual fixations in the monkey and the control strategies used to implement these constraints during head-free gaze saccades. Dual scleral search coil signals were used to compute 3-D orientation quaternions, two-dimensional (2-D) direction vectors, and 3-D angular velocity vectors for both the eye and head in three monkeys during the following visual tasks: radial to/from center, repetitive horizontal, nonrepetitive oblique, random (wide 2-D range), and random with pin-hole goggles. Although 2-D gaze direction (of Es) was controlled more tightly than the contributing 2-D Hs and Eh components, the torsional standard deviation of Es was greater (mean 3.55 degrees ) than Hs (3.10 degrees ), which in turn was greater than Eh (1.87 degrees ) during random fixations. Thus the 3-D Es range appeared to be the byproduct of Hs and Eh constraints, resulting in a pseudoplanar Es range that was twisted (in orthogonal coordinates) like the zero torsion range of Fick coordinates. The Hs fixation range was similarly Fick-like, whereas the Eh fixation range was quasiplanar. The latter Eh range was maintained through exquisite saccade/slow phase coordination, i.e., during each head movement, multiple anticipatory saccades drove the eye torsionally out of the planar range such that subsequent slow phases drove the eye back toward the fixation range. The Fick-like Hs constraint was maintained by the following strategies: first, during purely vertical/horizontal movements, the head rotated about constantly oriented axes that closely resembled physical Fick gimbals, i.e., about head-fixed horizontal axes and space-fixed vertical axes, respectively (although in 1 animal, the latter constraint was relaxed during repetitive horizontal movements, allowing for trajectory optimization). However, during large oblique movements, head orientation made transient but dramatic departures from the zero-torsion Fick surface, taking the shortest path between two torsionally eccentric fixation points on the surface. Moreover, in the pin-hole goggle task, the head-orientation range flattened significantly, suggesting a task-dependent default strategy similar to Listing's law. These and previous observations suggest two quasi-independent brain stem circuits: an oculomotor 2-D to 3-D transformation that coordinates anticipatory saccades with slow phases to uphold Listing's law, and a flexible "Fick operator" that selects head motor error; both nested within a dynamic gaze feedback loop.     

Multiple cerebral metastases: detectability with Gd-DTPA-enhanced MR imaging

Sixteen patients with suspected cerebral metastases were studied with magnetic resonance (MR) imaging before and after the intravenous administration of 0.1 mmol/kg of gadolinium diethylenetriaminepenta-acetic acid. The images were interpreted blindly by two neuroradiologists; all clinical, radiologic (computed tomographic and MR imaging), and pathologic data were reviewed to arrive at a final "best diagnosis," which was then compared with the prior blinded interpretations. Of seven patients found to have multiple metastases, six (86%) had at least one tumor nodule depicted by postinfusion MR imaging that was missed by one or both observers on review of preinfusion images alone. Lesions missed on preinfusion studies were usually small nodules hidden by or not detected next to regions of high-signal edema thought to be related to the adjacent tumor nodule. The authors believe that contrast enhancement improves detection of metastatic foci with MR imaging and that the findings indicate broader implications for the detection of multiple lesions from other causes.     

Osteopetrosis: MR characteristics at 1.5 T

Four patients with proved osteopetrosis (three with the infantile malignant form and one with the benign form) were examined with magnetic resonance imaging at 1.5 T. All patients were studied in the coronal and sagittal planes using both short and long repetition time/echo time sequences. The infantile malignant form was characterized by a complete lack of signal from the marrow alternating with a signal intensity equivalent to that of the intervertebral disks, resulting in a "stepladder" appearance. In the benign form or after successful marrow transplantation in the infantile malignant form, intermediate or high signal intensity in the vertebrae was noted, suggesting the presence of some marrow elements.     

Medical library education in China

This paper describes the establishment of faculties of medical library and information science in four of the national medical universities in the People's Republic of China. These faculties were established in the mid-1980s, and each is fully integrated into its university. Students receive three years of non-clinical medical training followed by two years of training in library and information science. The first students to follow this five-year curriculum will graduate in 1992.     

Transmission of Ovine Herpesvirus 2 in Lambs

The pattern of acquisition of ovine herpesvirus 2 (OHV-2) infection in lambs was examined by a competitive-inhibition enzyme-linked immunosorbent assay and PCR. Newborn lambs (n = 118) did not exhibit antibody at birth. Viral DNA in peripheral blood leukocytes was detected in only 3% (n = 77) of newborn lambs before suckling. After nursing, viral DNA was sporadically present in about 10 to 20% of lambs until about 3 months of age. Thereafter, strong DNA signals began to appear in increasing numbers of lambs, reaching 100% by 5.5 months of age. Viral DNA in nasal secretions began to be detectable in about 30% of lambs at 5.5 months of age, achieved significant levels in 88% of lambs by 7.5 months of age, and then declined. The kinetics of the humoral immune response in lambs paralleled those of viral DNA in nasal secretions but did not parallel its presence in blood leukocytes. In the experiment to define the time of infection of OHV-2 in lambs, all five lambs separated from the flock at 2.5 months of age remained uninfected until the termination of the experiment at 1 year of age. In contrast, lambs weaned at 2.5 months of age and returned to the flock had become infected at 3.5 months of age. Weaning and separation from the flock at 3.5 months of age did not prevent infection. The study showed that OHV-2 infection does not commonly occur in perinatal lambs and that OHV-2-free sheep can be established by separation of lambs at the proper time, which has important implications for potential control measures.