Vagus nerve stimulation for depression: rationale, anatomical and physiological basis of efficacy and future prospects.

Treatment-resistant depression (TRD) is a major public health concern due to its high costs to society. One of the novel approaches for the treatment of depression is the vagus nerve stimulation (VNS). Therapeutic brain stimulation through delivery of pulsed electrical impulses to the left cervical vagus nerve now has established safety and efficacy as an adjunct treatment for medication-resistant epilepsy and has recently been approved as an adjunct long-term treatment for chronic or recurrent depression. There is considerable evidence from both animal and human neurochemical and neuroimaging studies, that the vagus nerve and its stimulation influence limbic and higher cortical brain regions implicated in mood disorders, providing a rationale for its possible role in the treatment of psychiatric disorders. Clinical studies (open-label and comparator with treatment in naturalistic setting) in patients with TRD have produced promising results, especially when the response rates at longer-term (one- and two-year) follow-up time points are considered. Ongoing research efforts will help determine the place of VNS in the armament of therapeutic modalities available for major depression.

Biology of the X chromosome.

The biology of the X chromosome is unique, as there are two Xs in females and only a single X in males, whereas the autosomes are present in duplicate in both sexes. The presence of only a single autosome, which can occur as a result of an error in meiotic segregation, is invariably an embryonic lethal event. Monosomy for the X chromosome is viable because of dosage compensation, a system found in all organisms with an X:Y form of sex determination, which brings about equality of expression of most X-linked genes in females and males. In mammals, the dosage compensation system involves silencing of most of the genes on one X chromosome; it is called X chromosome inactivation. In this review, we focus first on recent advances in our understanding of the molecular basis of the X inactivation mechanism. Then we consider an unusual feature of X inactivation, the mosaic nature of the female and subsequent exposure to somatic cell selection.

Comparative methylation analysis of murine transgenes that undergo or escape X-chromosome inactivation.

We analyzed an X-linked metallothionein-vasopressin (MTVP) fusion transgene that undergoes X-chromosome inactivation (X inactivation) and an X-linked transferrin (TFN) transgene that escapes X inactivation with respect to methylation in the 5' regulatory regions. The MTVP transgene promoter region is unmethylated when the transgene is on the active X chromosome and methylated when on the inactive X chromosome. Interestingly, the MTVP transgene is not detectably transcribed from the male X chromosome, although it is unmethylated, consistent with its availability for transcription. The TFN transgene promoter region is hypomethylated on both the active and inactive X chromosomes, consistent with its expression from both chromosomes. The TFN and MTVP transgenes have been mapped to chromosomal regions D and C, respectively, by fluorescence in situ hybridization. These observations are discussed in the context of our understanding of the role of DNA methylation in the spread and maintenance of X-chromosome inactivation.

Isolation and characterization of radiation-reduced hybrids containing portions of the proximal long arm of the human X chromosome: identification of hybrids containing the Menkes' disease locus.

The proximal long arm of the human X chromosome (Xcen----Xq13) encompasses an estimated 23 megabases of DNA and contains numerous identified genetic loci. In order to generate a highly enriched source of DNA from this region, radiation-reduced human-hamster hybrids were constructed and screened to identify those that contained at least part of proximal Xq. Eight such hybrids were identified and characterized by Southern blot and fluorescence in situ hybridization analyses to determine more precisely the human DNA complement in each. One hybrid contains the entire proximal long arm and will be useful for mapping Xcen----Xq13 in its entirety and for localizing genes within this region. Another hybrid contains a smaller portion of the proximal long arm that includes the region reported to contain the gene for Menkes' disease.

Fetal choroid plexus cysts: beware the smaller cyst.

Current literature suggests that amniocentesis be performed on fetuses with simple choroid plexus cysts only when such cysts are 1.0 cm or greater in diameter and bilateral. At retrospective analysis of 3,769 patients, choroid plexus cysts were noted in 87 (2.3%), representing a rate three times greater than that of previous reports. Eight-three patients underwent amniocentesis. Six (7.2%) had abnormal karyotypes. Four patients had the commonly associated chromosomal abnormality trisomy 18. Two had karyotypes not usually associated with this problem: mosaic Turner syndrome and trisomy 21. Of the six patients with abnormal karyotypes, one had a 4-mm-diameter unilateral choroid plexus cyst and three had bilateral cysts of 3-5 mm. Only one patient with a 16-mm cyst had any associated structural abnormality discovered at rigorous ultrasound examination. Karyotyping may be necessary in fetuses with small choroid plexus cysts. Deciding which patients should be encouraged to undergo amniocentesis is made more complex by these data.

Normal length of fetal kidneys: sonographic study in 397 obstetric patients.

This study was done to measure normal lengths of fetal kidneys sonographically during pregnancy. Knowledge of these measurements may allow earlier diagnosis of a variety of abnormalities. The greatest length of each of 498 kidneys in 397 consecutive fetuses between 18 and 41 weeks gestation was measured on sonograms. Gestational ages were determined by last menstrual period and biometry; significant discrepancies led to case exclusion. Abnormal fetuses, twins, offspring of diabetic mothers, and fetuses with renal pelvic dilatation of 4 mm or greater were excluded to avoid any questionable measurements. The results show that mean lengths are greater and confidence intervals are wider than previously reported. Renal lengths are similar to those reported in premature and full-term neonates. Strong correlation exists between renal length and gestational age, determined by biparietal diameter, femoral length, and abdominal circumference, and an average of the three. No significant difference was found between right and left renal lengths in fetuses in whom both kidneys were imaged. Average renal lengths are significantly different when compared across the range of gestational ages (p less than .001). No correlation is seen (r = .00) between parental height or weight and fetal renal length. Our results show that fetal renal lengths are longer than previously reported.

Nucleotide sequence of the 3' nuclease-sensitive region of the human phosphoglycerate kinase 1 (PGK1) gene.

Many genes are known to have nuclease-sensitive sites and/or control sequences in their 3' flanking regions, but for very few genes has this region been sequenced. Previously, we mapped specific, gene activity-dependent DNAase I- and MspI-sensitive sites at the 3' end of the human X-linked housekeeping gene phosphoglycerate kinase (PGK1). Sequence information presented here shows that the 3' nuclease-sensitive site maps precisely to an Alu sequence and near a "BKM" repeat. This is the first report of an Alu sequence that has alternative chromatin configurations depending on gene activity.

Rapid diagnosis of thoracic aortic transection using intravenous digital subtraction angiography.

Rupture of the thoracic aorta associated with blunt trauma remains a frequently lethal injury. Although increasing numbers of patients with ruptured aortas are surviving to reach the hospital, the in-hospital mortality attending this injury remains high. Death due to transected aorta has been related to a delay in diagnosis. In an attempt to decrease the time necessary for diagnosis of this injury, we studied 50 patients using intravenous digital subtraction angiography (IVDSA) and conventional biplane angiography. We found that IVDSA was significantly faster than conventional biplane angiography, and that when IVDSA films are of diagnostic quality, they are sufficient to reliably demonstrate the presence of traumatic aortic transection. Our study was too small to establish whether IVDSA is a sufficiently sensitive test to exclude aortic injury. Further studies in this area need to be performed.

A chicken transferrin gene in transgenic mice escapes X-chromosome inactivation.

Mammalian X-chromosome inactivation involves a coordinate shutting down of physically linked genes. Several proposed models require the presence of specific sequences near genes to permit the spread of inactivation into these regions. If such models are correct, one might predict that heterologous genes transferred onto the X chromosome might lack the appropriate signal sequences and therefore escape inactivation. To determine whether a foreign gene inserted into the X chromosome is subject to inactivation, transgenic mice harboring 11 copies of the complete, 17-kilobase chicken transferrin gene on the X chromosome were used. Male mice hemizygous for this insert were bred with females bearing Searle's translocation, an X-chromosome rearrangement that is always active in heterozygous females (the unrearranged X chromosome is inactive). Female offspring bearing the Searle's translocation and the chicken transferrin gene had the same amount of chicken transferrin messenger RNA in liver as did transgenic male mice or transgenic female mice lacking the Searle's chromosome. This result shows that the inserted gene is not subject to X-chromosome inactivation and suggests that the inactivation process cannot spread over 187 kilobases of DNA in the absence of specific signal sequences required for inactivation.

Viridans streptococcal endocarditis: clinical, microbiological, and echocardiographic correlations.

Infections caused by species within the viridans streptococci have been associated with different clinical characteristics. We studied 36 patients with viridans streptococcal endocarditis. Complications were seen in 10 (32%) of 31 patients with native valve endocarditis and four (80%) of five with prosthetic valve endocarditis and included death in two, valve replacement in six, persistent infection in three, emboli in two, and congestive heart failure in nine. Two-dimensional echocardiograms demonstrated vegetations in 26 (72%) of 36, flail mitral valves in seven, disruption of aortic valve prosthesis in one, and perivalvular abscesses in three (two Streptococcus sanguis I and one Streptococcus intermedius I). All twelve patients with native valve endocarditis who suffered complications had vegetations detected by two-dimensional echocardiography, whereas seven patients with native valve endocarditis without vegetations, as detected by two-dimensional echocardiography, had no complications (P = .03). We found no significant correlation between streptococcal species and clinical outcome. To confirm our identifications, we sent 16 identical viridans streptococcal endocarditis isolates to five institutions; only three of 16 were identified as the same species by all five institutions. We conclude that viridans streptococcal endocarditis can be associated with a virulent clinical course and that there is marked variability in species designations of individual strains by different laboratories.

Congenital intracardiac rhabdomyoma: prenatal detection by echocardiography, perinatal management, and surgical treatment.

A case of a newborn infant with an intracardiac tumor, detected in utero by fetal echocardiography at 30 weeks gestation, is presented. The prenatal evaluation by serial fetal echocardiograms and nonstress tests is described. In the perinatal period, ventricular tachycardia occurred and was successfully managed with antiarrhythmic medications. At 20 months of age, a right ventricular rhabdomyoma was removed at open heart surgery. The patient represents the earliest in utero detection of a fetal intracardiac tumor with successful postnatal outcome.

The utilization of the human phosphoglycerate kinase gene in the investigation of X-chromosome inactivation.

The X-linked human Pgk gene has been cloned and partially characterized, and some preliminary results have been obtained regarding active vs. inactive gene comparisons of chromatin structure and methylation patterns. As yet we can say nothing definitive about what role, if any, these differences may play in X inactivation. The studies showing that DNA from the inactive X chromosome in mature somatic cells does not function in transformation of the Hprt gene strongly imply modification of the inactive X chromosome at the DNA level. However, methylation studies with the Hprt, Gd Pgk genes have revealed a complexity of methylation patterns including hypermethylation of parts of the active X gene. Resolution of just what difference is critical in expression, differentiating between cause and effect, and extrapolating to the spreading and initiation aspects of X inactivation are still, unfortunately, long-range goals. The Pgk system may be of special value in unraveling some of these difficult questions. A unique autosomal Pgk locus exists and should allow an informative comparison between an X-linked housekeeping gene and an autosomal, tissue-specific gene encoding proteins of identical enzymatic function. The proximity of Pgk to the X-inactivation control center may be useful in identifying the starting point of this very important event in early mammalian development.