A new COL3A1 mutation in Ehlers–Danlos syndrome type IV

The vascular type of the Ehlers–Danlos syndrome (Ehlers–Danlos syndrome type IV, EDS IV; OMIM #130050) is a rare connective tissue disorder with autosomal dominant transmission caused by mutations in the COL3A1 gene resulting in increased fragility of connective tissue with arterial, intestinal, and uterine ruptures and premature death. We present a 28‐year‐old female who in addition to typical EDS IV symptoms had severe peripheral artery occlusive disease (PAOD) and subtotal stenosis of the abdominal aorta. COL3A1 sequencing resulted in detection of an as yet undescribed mutation in exon 36 at position 2465 leading to a nucleotide replacement (c.2465G>C; p.G822A). Ultrastructural analysis of a skin biopsy revealed abnormal morphology and distribution of dermal collagen fibres. We conclude that PAOD is a possible manifestation of EDS IV and that further research is required to define its true prevalence among patients with EDS IV and its molecular pathology including genotype–phenotype correlation.     

Standardizing Postoperative Complications—Validating the Clavien-Dindo Complications Classification in Cardiac Surgery

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Transfer across the human blood-brain barrier: Evidence for capillary recruitment and for a paradox glucose permeability increase in hypocapnia

The present study was undertaken to investigate whether there is intermittency of capillary flow in the human brain, i.e., whether more capillaries open up at high blood flow thus increasing the surface for diffusional exchange. Unidirectional transfer across the blood-brain barrier of labeled D-glucose, l-phenylalanine, l-leucine, thiourea, and propranolol was measured using the indicator diffusion method with labeled Na⁺, Cl^?, and chelated In as impermeable reference substances. Forty-three patients needing carotid angiography were studied in different situations, rest, hyperventilation, hypercapnia, hypo/hypertension (within the limits of autoregulation). Some older data on the seizure situation are included. Cerebral blood flow (CBF) was measured concomitantly. In situations with high blood flow, extraction (E) decreased and the permeability surface area product (PS) increased for both the lipophilic substances and for those transferred by carrier mechanism. With low CBF the reverse happened except for an unexpected PS increase for glucose in hyperventilation. Variations of PS in parallel with CBF are evidence of capillary recruitment which constitutes a more efficient way of increasing tissue supply. PS and E remained constant with a constant CBF even when arterial blood pressure was changed, indicating that autoregulatory mechanisms do not affect the diffusional exchange surface and probably take place at the arteriolar level. PS for glucose increased in hyperventilation perhaps as an expression of a pH dependence of its carrier.     

Characteristics of recovery of adrenocortical function after treatment for Cushing's syndrome due to pituitary or adrenal adenomas

OBJECTIVE: Surgical cure of Cushing's syndrome (CS) is followed by adrenocortical insufficiency, which may be long-lasting. The aim was to elucidate recovery of adrenocortical function, defined as a normal cortisol response to ACTH stimulation, and the relation to ACTH in patients cured for CS due to pituitary Cushing's disease (CD) or adrenal (AA) adenomas. DESIGN: A retrospective study including 32 patients considered surgically cured for CS (18 CD, 14 AA). RESULTS: Twelve (67%) patients with CD recovered within median 24 months (range 7 months-4(1)/(2) years) whereas six did not recover within 3-12 years. Plasma ACTH (p-ACTH) at time of recovery was not different from p-ACTH in patients not recovering (P = 0.9). Eleven (79%) patients with AA recovered within 24 months (10 months-4 years) whereas three did not recover within 4-10 years. p-ACTH at time of recovery was higher compared to patients not recovering (P < 0.04). No differences were observed comparing CD and AA patients concerning preoperative 24-h urinary free cortisol (UFC) excretion, postoperative unstimulated s-cortisol or recovery time. By contrast, p-ACTH measured at time of recovery was higher in AA compared to CD (median 12.3 vs. 4.6 pmol/l) (P < 0.001), whereas plasma dehydroepiandrosterone sulfate (p-DHEAS) was lower in AA compared to CD (median 300 vs. 1500 nmol/l) (P = 0.02). CONCLUSION: Recovery of secondary adrenal insufficiency is a slow process in both CD and AA. ACTH measured at time of recovery was significantly higher and DHEAS significantly lower in patients with AA compared to CD, which may suggest different mechanisms of the recovery process and different set points in the glucocorticoid feedback inhibition of ACTH secretion.     

The risk of major cardiovascular events for adults with transfemoral amputation

Background

It is well-known that the risk of cardiac disease is increased for those with lower-limb amputations, likely as a result of the etiology of the amputation. Using a longitudinal population-based dataset, we examined the association between transfemoral amputation (TFA) status and the risk of experiencing a major cardiac event for those undergoing either dysvascular or traumatic amputations. The association of receiving a prosthesis with the risk of experiencing a major cardiac event was also examined.

Methods

Study Population: All individuals with TFA (N 162), i.e. knee disarticulation and transfemoral amputation, residing in Olmsted County, MN, between 1987 and 2014. Each was matched (1:10 ratio) with non-TFA adults on age, sex, and duration of residency.Data Analysis: A competing risk Cox proportional hazard model was used to estimate the relative likelihood of an individual with a TFA experiencing a major cardiac event in a given time period as compared to the matched controls. The cohort was divided by amputation etiology: dysvascular vs trauma/cancer. Additional analysis was performed by combining all individuals with a TFA to look at the relationship between prosthesis receipt and major cardiac events.

Results

Individuals with a dysvascular TFA had an approximately four-fold increased risk of a cardiac event after undergoing an amputation (HR 3.78, 95%CI: 3.07–4.49). These individuals also had an increased risk for non-cardiac mortality (HR 6.27, 95%CI: 6.11–6.58). The risk of a cardiac event was no higher for those with a trauma/cancer TFA relative to the able-bodied controls (HR 1.30, 95%CI: 0.30–5.85). Finally, there was no difference in risk of experiencing a cardiac event for those with or without prosthesis (HR 1.20, 95%CI: 0.55–2.62).

Conclusion

The high risk of initial mortality stemming from an amputation event may preclude many amputees from cardiovascular disease progression. Amputation etiology is also an important factor: cardiac events appear to be more likely among patients with a dysvascular TFA. Providing a prosthesis does not appear to be associated with a reduced risk of a major cardiac event following amputation.

     

Normocomplementaemic urticarial vasculitis: effective treatment with omalizumab

We report two patients with normocomplementaemic urticarial vasculitis with impressive response to omalizumab. This contrasts recent reports on hypocomplementaemic urticarial vasculitis syndrome, highlighting the need for clinical trials of omalizumab in normocomplementaemic urticarial vasculitis.