Perioperative outcome, long-term mortality and time trends in elderly patients undergoing low-, intermediate- or major non-cardiac surgery.

BACKGROUND: Decision-making whether older patients benefit from surgery can be a difficult task. This report investigates characteristics and outcomes of a large cohort of inpatients, aged 80 years and over, undergoing non-cardiac surgery. METHODS: This observational study was performed at a tertiary university medical centre in the Netherlands. Patients of 80 years or older undergoing elective or urgent surgery from January 2004 to June 2017 were included. Outcomes were length of stay, discharge destination, 30-day and long-term mortality. Patients were divided into low-, intermediate and high-risk surgery subgroups. Univariable and multivariable logistic regression were used to evaluate the association of risk factors and outcomes. Secondary outcomes were time trends, assessed with Mantel-Haenszel chi-square test. RESULTS: Data of 8251 patients, undergoing 19,027 surgical interventions were collected from the patients' medical record. 7032 primary procedures were suitable for analyses. Median LOS was 3 days in the low-risk group, compared to six in the intermediate- and ten in the high-risk group. Median LOS of the total cohort decreased from 5.8 days (IQR 1.9-14.5) in 2004-2007 to 4.6 days (IQR 1.9-9.0) in 2016-2017. Three quarters of patients were discharged to their home. Postoperative 30-day mortality in the low-risk group was 2.3%. In the overall population 30-day mortality was high and constant during the study period (6.7%, ranging from 4.2 to 8.4%). CONCLUSION: Patients should not be withheld surgery solely based on their age. However, even for low-risk surgery, the mortality rate of more than 2% is substantial. Deciding whether older patients benefit from surgery should be based on the understanding of individual risks, patients' wishes and a patient-centred plan.

Ebstein's anomaly may be caused by mutations in the sarcomere protein gene MYH7.

Ebstein's anomaly is a rare congenital heart malformation characterised by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. Associated abnormalities of left ventricular morphology and function including left ventricular noncompaction (LVNC) have been observed. An association between Ebstein's anomaly with LVNC and mutations in the sarcomeric protein gene MYH7, encoding ß-myosin heavy chain, has been shown by recent studies. This might represent a specific subtype of Ebstein's anomaly with a Mendelian inheritance pattern. In this review we discuss the association of MYH7 mutations with Ebstein's anomaly and LVNC and its implications for the clinical care for patients and their family members.

Duchenne/Becker muscular dystrophy in the family: have potential carriers been tested at a molecular level?

Duchenne muscular dystrophy (DMD) is the most common inherited neuromuscular disease. After identification of the mutation in the index patient, family members can be reliably investigated. Carriers should be informed about their risk of having offspring with the disease and about their own risk for cardiomyopathy for which regular cardiac surveillance is recommended. In a small country like the Netherlands with well-organized genetic services, one would expect that most DMD families are adequately informed about the above mentioned risks for carriers. We have investigated whether women at risk had been tested at a molecular level. In the national Duchenne/Becker database 311 DMD and 99 Becker muscular dystrophy (BMD) patients had been registered up to 1 July 2009. These patients were asked to give information about the number of sisters and maternal aunts of the DMD/BMD patient and anything that was known about their genetic status and that of the mother. This information was compared with the information known at the genetic laboratory. Thirty-five of 104 adult sisters/maternal aunts of DMD patients with a 50% risk of being a carrier and 45 of 148 adult women with a 4.3% risk because of germ line mosaicism for DMD had not been tested by DNA analysis. Our study indicates that about one third of the potential carriers have not been tested. Given the possible far-reaching clinical consequences of being a carrier, further studies are needed to investigate the reasons why potential female carriers have not been tested.

Becker muscular dystrophy patients with deletions around exon 51; a promising outlook for exon skipping therapy in Duchenne patients.

Theoretically, 13% of patients with Duchenne muscular dystrophy may benefit from antisense-mediated skipping of exon 51 to restore the reading frame, which results in the production of a shortened dystrophin protein. We give a detailed description with longitudinal follow up of three patients with Becker muscular dystrophy with in-frame deletions in the DMD gene encompassing exon 51. Their internally deleted, but essentially functional, dystrophins are identical to those that are expected as end products in DMD patients treated with the exon 51 skipping therapy. The mild phenotype encourages further development of exon 51 skipping therapy.

Recurrence risk due to germ line mosaicism: Duchenne and Becker muscular dystrophy.

The presence of multiple affected offspring from apparently non-carrier parents is caused by germ line mosaicism. Although germ line mosaicism has been reported for many diseases, figures for recurrence risks are known for only a few of them. In X-linked Duchenne and Becker muscular dystrophies (DMD/BMD), the recurrence risk for non-carrier females due to germ line mosaicism has been estimated to be between 14% and 20% (95% confidence interval 3-30) if the risk haplotype is transmitted. In this study, we have analyzed 318 DMD/BMD cases in which the detected mutation was de novo with the aim of obtaining a better estimate of the 'true' number of germ line mosaics and a more precise recurrence risk. This knowledge is essential for genetic counseling. Our data indicate a recurrence risk of 8.6% (4.8-12.2) if the risk haplotype is transmitted, but there is a remarkable difference between proximal (15.6%) (4.1-27.0) and distal (6.4%) (2.1-10.6) deletions. Overall, most mutations originated in the female. Deletions occur more often on the X chromosome of the maternal grandmother, whereas point mutations occur on the X chromosome of the maternal grandfather. In unhaplotyped de novo DMD/BMD families, the risk of recurrence of the mutation is 4.3%.

Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study.

Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders.

Somatic mosaicism of a point mutation in the dystrophin gene in a patient presenting with an asymmetrical muscle weakness and contractures.

We describe a patient with somatic mosaicism of a point mutation in the dystrophin gene causing benign muscular dystrophy with an unusual asymmetrical distribution of muscle weakness and contractures. To our knowledge this is the first patient with asymmetrical weakness and contractures in an ambulatory patient with a dystrophinopathy.

Rate of visual field loss in progressive glaucoma.

OBJECTIVE: To investigate the rate of visual field (VF) loss in progressive glaucoma. SETTING: Outpatient department, nonreferral base. METHODS: A cohort of 34 patients with normal-pressure glaucoma (NPG), 68 patients with primary open-angle glaucoma (POAG), and 125 patients with ocular hypertension (OHT) were followed up for an average of 9 years. Visual fields were obtained annually with automated perimetry. The rate of VF loss as a percentage per year was calculated. RESULTS: Twenty-three eyes with NPG, 31 with POAG, and 10 with OHT showed progression of VF loss. The mean (+/-SD) rates of VF deterioration were 3.7%+/-3.3% per year in NPG, 2.5%+/-1.8% in POAG, and 2.3%+/-1.3% in OHT converting to POAG, and did not differ significantly. No difference in the rate of VF loss was found between eyes with and without optic disc hemorrhages (2.7%+/-2.9% and 3.1%+/-2.1%, respectively). The rate of VF loss was not related to the initial VF status. The rate of VF loss between the superior and inferior hemifields was correlated in patients with NPG (r(s) = 0.67, P = .04). Comparison of visual field loss with linear regression analysis showed significant slopes in only 37.5% of eyes with progression, which had a progression rate of 4.2%+/-3.0%. CONCLUSIONS: The rate of VF loss did not differ between patients with NPG and POAG. The rate of deterioration was related neither to initial VF status nor to the presence of disc hemorrhages. Linear regression is applicable only in a portion of the patients who have progression of VF loss.

Monozygotic twin brothers with the fragile X syndrome: different CGG repeats and different mental capacities.

Little is known about the mechanism of CGG instability and the time frame of instability early in embryonic development in the fragile X syndrome. Discordant monozygotic twin brothers with the fragile X syndrome could give us insight into the time frame of the instability. We describe monochorionic diamniotic twin brothers with the fragile X syndrome who had different CGG repeats and different mental capacities, whereas the normal mother had a premutation. The more retarded brother had a full mutation in all his cells and no FMR-1 protein expression in lymphocytes, whereas the less retarded brother had 50%/50% mosaicism for a premutation and full mutation and FMR-1 protein expression in 26% of his lymphocytes. The differences in repeat size could have arisen either before or after the time of splitting. The time of splitting in this type of twin is around day 6-7. Given the high percentage of mosaicism, we hypothesise that the instability started before the time of splitting at day 6-7.

A near false-negative finding of mosaic trisomy 21--a cautionary tale.

We report the finding of a mosaic trisomy 21 restricted to the long-term culture of chorionic villi and to one amniotic fluid culture which, if interpreted according to the standard rules for the authentication of mosaicism, would have resulted in a false-negative result. The definitive diagnosis of mosaic Down syndrome was eventually confirmed by cordocentesis and by post-abortion fibroblast cultures.

Deterioration of visual fields in patients with glaucoma with and without optic disc hemorrhages.

OBJECTIVE: To evaluate visual field deterioration in patients with glaucoma with and without optic disc hemorrhages (DHs). DESIGN: A prospective study at quarterly base involving annual perimetry; mean follow-up of 9 years. SETTING: Outpatient department, nonreferral basis. PATIENTS: Sixty-eight patients with primary open-angle glaucoma, 34 with normal pressure glaucoma (NPG), and 125 with ocular hypertension. RESULTS: Visual field deterioration occurred in 32%, 32%, and 6% of the patients without DHs who had NPG, primary open-angle glaucoma, or ocular hypertension, respectively, while visual field deterioration occurred in 80%, 89%, and 14% of patients with DH, respectively. Cox proportional hazards ratio(CHR) for deterioration in patients with vs patients without DHs was 5.4 for NPG (P<.01) and 3.6 for primary open-angle glaucoma (P<.01). In patients with NPG and DHs, ipsilateral eyes with DHs deteriorated in 58%, while contralateral eyes without DHs deteriorated in 11% (CHR, 8.9; P<.04). For primary open-angle glaucoma and ocular hypertension, progression did not differ between eyes with DHs and contralateral eyes without DHs. Mean (+/-SD) interval between DHs and ipsilateral visual field deterioration was 3.1+/-1.7 years. No difference in the proportion of eyes progressing after single or recurrent DHs was noted. The position of DHs was related to the site of the visual field loss in 44% of the eyes. CONCLUSIONS: The presence of DHs increased the risk of visual field deterioration. Disc hemorrhages were indicative only of deterioration in ipsilateral eyes in patients with NPG.

Body wall defects in two sibs.

We describe 2 sibs, a male fetus with an unusual lumbar hernia and spina bifida occulta, and a female fetus with a median abdominoschisis. The first fetus had some signs of lumbocostovertebral syndrome (LCVS), which consists of a congenital lumbar hernia and associated abnormalities such as absent or hypoplastic ribs, hemivertebrae, and scoliosis. Abdominoschisis has not been described in LCVS, and the given abnormalities in the 2 sibs have not been published to date. One can hypothesize that vascular disruption of a somite or a group of somites may result in the described abdominal wall defects. We conclude that these abnormalities could be coincidental in the 2 sibs or could have a related, probably multifactorial, cause.

Mosaic tetrasomy 15q25-->qter in a newborn infant with multiple anomalies.

We describe a premature boy with metopic craniosynostosis, facial anomalies, atrial-septal defect, hydronephrosis and flexion contractures of lower limbs, and mosaic tetrasomy 15q25-->qter. The extra chromosome material was present in the form of an acentric marker. A number of clinical manifestations observed in this child were also found in 3 previously reported patients who were trisomic for the same part of chromosome 15 and in 2 patients who were tetrasomic for a larger segment of 15q.

Coherence in localized visual evoked potentials (VEPs) to spatial stimulus attributes (orientation and displacement) in man.

The purpose of this study was to compare visual evoked potentials (VEPs) of striate-peristriate and Cz to posterior parietal, especially IPL's supramarginal (Su) and angular (Ang, Ano, and Ant) leads in response to human face spatial attributes attend-task, to assess the concern of the former with basic features versus the latter's spatial attributes "rotated" rightwards, leftwards, or oblique (unusual angle of sight) or nodal one (eye)- and two-item, eye/mouth displacement. Monopolar cranially derived VEPs were recorded bihemispherically from six adults using 12 electrode arrays 1.5 to 2 cm apart. Subjects were instructed to fixate a marking on the monitor at a nodal eyebrow region, while attending the stimulus that was computer displayed for 200 or 300 ms, and followed by mask. Analysis was made on the first 240 ms of the records after stimulus onset; the test was compared to "full face," the hypothesized control. Localized VEP changes were observed task-bound and bihemispherically coherent in parietal leads, especially Ang, Ano, and Su. The early negativity of the "full face" control was replaced by an early positive wave with onset latencies of 70 +/- 15 ms, significantly shorter (p < 0.01) than the striate's 90 +/- 20 ms. The changes were observed for both rotation and displacement. The changes in the angular leads (Ano and Ang) are consistent with the encoding of spatial attributes of orientation and nodal face items displacement. Differentiation of direction and degree of rotation, "seen from above" versus "seen from below," largely encoded by the right Su. The composite double-item eye and displaced or obliquely rotated induced extended coherent activity in parietal leads. Oz, peristriate, and Cz showed no such changes. No attempt is made to imply source localization; we claim parietal localized and coherency of the VEP changes suggest high-order early processing of human face attributes. This occurs by a relatively fast pathway. The "triggers" for the changes are direction and degree of rotation or of displacement rather than actual geometry of the stimulus.

Jumping translocation in a newborn boy with dup(4q) and severe hydrops fetalis.

We report on the unusual cytogenetic findings in a newborn boy with severe hydrops fetalis. He has a mosaic for 2 unbalanced chromosome rearrangements: a der(18)-t(4;18)(q31;q23) and a der(18)t(4;18)(q31;p11). As a result, this patient had a duplication of 4q31-qter in all cells, and was possibly monosomic for the distal ends of 18p and 18q, respectively in the 2 cell lines. Since in both rearrangements the same chromosome 4 segment was translocated to 2 different chromosome regions, we consider the present finding as a peculiar type of jumping translocation.

Cumulative incidence of patients with disc hemorrhages in glaucoma and the effect of therapy.

PURPOSE: In this longitudinal study, the cumulative incidence of patients with glaucoma and disc hemorrhages was investigated. A possible effect of glaucoma therapy on the incidence rate of disc hemorrhages was evaluated. METHODS: A group consisting of 68 patients with primary open-angle glaucoma (POAG), 34 with normal-pressure glaucoma, and 125 with suspected glaucoma (mean follow-up, 7.3 +/- 2.5 years; range 3-13 years) was observed closely with quarterly examinations. RESULTS: In normal-pressure glaucoma, the cumulative incidence of patients with disc hemorrhages was 35.3%, which was significantly higher than for those with POAG (10.3%; P < 0.01) and for those with suspected glaucoma (10.4%; P < 0.001). The mean follow-up period before a first disc hemorrhage was detected was 2.5 +/- 2.8 years. In the bleeders, recurrent disc hemorrhages were observed in 67% of the patients with normal-pressure glaucoma, 29% of those with POAG, and 54% of glaucoma suspects. In normal-pressure glaucoma, therapy had no effect on the incidence rate of disc hemorrhages. In glaucoma suspects, a significant reduction of the incidence rate of disc hemorrhages per year (0.11 +/- 0.04) was observed during episodes with therapy compared with episodes without (0.43 +/- 0.15; P < 0.05). A concept of two populations (i.e., one with disc hemorrhages and the other never having them) seems to be valid for normal-pressure glaucoma, but not for POAG and suspected glaucoma. CONCLUSION: The cumulative incidence of initial disc hemorrhages increases with time in POAG and suspected glaucoma, but reaches a limit in normal-pressure glaucoma. Glaucoma therapy may reduce the incidence rate of all, initial and recurrent, disc hemorrhages in patients with high pressures, but not in patients with normal-pressure glaucoma.

[Phenylketonuria as a model system for DNA diagnosis of hereditary disorders]. / Fenylketonurie als modelsysteem voor DNA-diagnostiek van erfelijke aandoeningen.

Phenylketonuria (PKU), due to a defect in phenylalanine hydroxylase (PAH), is presented as a model system for computer-aided DNA diagnosis of genetic diseases. Eight different restriction fragment length polymorphism (RFLP) markers have been localized within the introns of the 90 kb PAH gene (located on chromosome 12). These RFLPs can be combined in 384 different ways and each combination has been defined as a particular haplotype. A special computer program has been developed to calculate the possible haplotype combinations in a PKU core family (index patient and parents), with the goal to derive unambiguously both the PAH and PKU alleles. Taking into account that participation of other members of the family (grandparents or brothers/sisters) is sometimes necessary, haplotyping by itself is sufficient to establish (or exclude) the PKU status of an individual in approximately eight out of ten PKU families.

Binocular depth reversals despite familiarity cues.

Stereoscopic depth can be reversed by interchanging the left- and right-eye views (pseudoscopy) when abstract stereograms are used, but not when stereograms contain natural objects or scenes. This resistance to reversal of depth has traditionally been attributed to familiarity with the shape of objects and the presence of monocular depth cues. However, when texture disparity is neutralized by making the texture perspective of surfaces identical for both eyes, even a highly familiar object, like a monocularly recognizable human face, appears as concave (nose pointing inwards) when viewed pseudoscopically.