The influence of diabetes on free flap transfer: I. Flap survival and microvascular healing.

Although recent clinical case presentations suggest that diabetes does not predispose free tissue transfers to increased risk of failure, this remains an open question. The present study used a syngeneic rat strain (Lewis) for free groin flap transplantations between normal rats and streptozotocin-induced diabetic rats (2 months' duration of symptoms), to investigate the influence of diabetes on flap transfer. Flap survival at 1 week, vascular patency, flap histology and ultrastructure, and scanning electron microscopy of anastomotic sites and of corrosion casts of flap vasculature were used as bases for comparison. No differences were found in comparisons of flap survival between any groups of transfer combinations (normal flap onto normal recipient, diabetic flap onto normal recipient, normal flap onto diabetic recipient, and diabetic flap onto diabetic recipient); 100% success was achieved in each group. No differences were found in histology or corrosion casts. Transmission electron microscopy revealed a thickening of the capillary basement membrane in rat diabetic skin after only 8 weeks of symptoms. This ultrastructural finding is consistent with similar capillary basement membrane thickening seen in many other tissues of short- and long-term diabetic animals and humans. Re-endothelialization across the arterial anastomosis at 2 weeks postoperatively was significantly faster in normal versus diabetic animals (p less than 0.05). The predominantly negative findings of this study support the application of free flap transfers in diabetic patients. It is concluded that reconstructive efforts involving free tissue transfer may not be contraindicated in diabetic patients.     

Muscle mass effect on arterial desaturation after maximal exercise.

We measured arterial oxygen saturation before and immediately after randomly allocated 6 min of "all-out" maximal arm cranking, treadmill running, and ergometer rowing in 10 men and women with a median maximal oxygen uptake of 4.47 (range 3.22-5.34) 1.min-1. Arterial saturation for oxygen was unaltered after arm cranking, but decreased 1.7 (-2.5-6.0) % (P less than 0.05) after running, and 2.2 (1.0-8.7) % (P less than 0.01) after rowing. Arterial saturation was inversely related to capillary blood lactate, which reached 11.8 (7.4-14.0), 12.6 (8.9-18 2), and 14.3 (12.0-19.3) mmol.l-1 (P less than 0.01), respectively, and arterial bicarbonate fell to 15.0 (13.0-23.6), 12.4 (7.2-20.4), and 10.8 (0.0-12.5) mmol.l-1 (P less than 0.01). Thus, pH decreased to 7.25 (7.22-7.40), 7.17 (6.95-7.35), and 7.09 (6.84-7.19) (P less than 0.01). When measured immediately post-exercise, arterial oxygen tension was unchanged or elevated from rest, eliminating the possibility that the arterial desaturation was caused by a pulmonary diffusion limitation. The results of this investigation show that arterial desaturation associated with maximal exercise takes place in proportion to the involved muscle mass, as do deviations in blood lactate, bicarbonate, and hydrogen concentrations.     

Safety of Intraventricular Hemorrhage (IVH) Thrombolysis Based on CT Localization of External Ventricular Drain (EVD) Fenestrations and Analysis of EVD Tract Hemorrhage

Background

The purpose of the study is to review the CT findings associated with ventriculostomy placement in regards to the safety of an EVD plus recombinant tissue plasminogen activator (rt-PA) for IVH.

Methods

A retrospective review was conducted for patients receiving intraventricular rt-PA for IVH from January 2004 to September 2009. Safety was assessed by the presence of EVD tract hemorrhage by CT at baseline after EVD placement, worsening hemorrhage after rt-PA, and CSF infection. IVH volumetrics were assessed by the Le Roux score and outcomes by Glasgow Outcome Scale and modified Rankin Scale.

Results

Twenty-seven patients received rt-PA for IVH. Median dose was 2 mg (range 0.3–8) and a median of two doses (range 1–17) were given. Worsening EVD catheter tract hemorrhage after rt-PA was 46.7 %, with a significantly higher incidence of worsening tract hemorrhage seen with incorrectly placed EVDs (p = 0.04). IVH hematoma burden decreased by a median Le Roux score of 10 (range 3–16) prior to rt-PA to 4 (range 0–16) after rt-PA. There were no central nervous system bacterial infections.

Conclusion

Intraventricular rt-PA appears to be relatively safe especially when all EVD fenestrations are within the ventricle and reduces IVH burden similar to other studies. We describe a CT-based EVD tract hemorrhage grading scale to evaluate EVD tract hemorrhage before and after thrombolysis, and a bone-window technique to evaluate EVD fenestrations prior to IVH thrombolysis. Further research is needed evaluating these imaging techniques in regard to intraventricular thrombolytic safety and EVD tract hemorrhage.     

How multiplicity determines entropy and the derivation of the maximum entropy principle for complex systems

The maximum entropy principle (MEP) is a method for obtaining the most likely distribution functions of observables from statistical systems by maximizing entropy under constraints. The MEP has found hundreds of applications in ergodic and Markovian systems in statistical mechanics, information theory, and statistics. For several decades there has been an ongoing controversy over whether the notion of the maximum entropy principle can be extended in a meaningful way to nonextensive, nonergodic, and complex statistical systems and processes. In this paper we start by reviewing how Boltzmann–Gibbs–Shannon entropy is related to multiplicities of independent random processes. We then show how the relaxation of independence naturally leads to the most general entropies that are compatible with the first three Shannon–Khinchin axioms, the -entropies. We demonstrate that the MEP is a perfectly consistent concept for nonergodic and complex statistical systems if their relative entropy can be factored into a generalized multiplicity and a constraint term. The problem of finding such a factorization reduces to finding an appropriate representation of relative entropy in a linear basis. In a particular example we show that path-dependent random processes with memory naturally require specific generalized entropies. The example is to our knowledge the first exact derivation of a generalized entropy from the microscopic properties of a path-dependent random process.Many statistical systems can be characterized by a macrostate for which many microconfigurations exist that are compatible with it. The number of configurations associated with the macrostate is called the phase-space volume or multiplicity, M. Boltzmann entropy is the logarithm of the multiplicity,and has the same properties as the thermodynamic (Clausius) entropy for systems such as the ideal gas (1). We set . Boltzmann entropy scales with the degrees of freedom f of the system. For example, for N noninteracting point particles in three dimensions, . Systems where scales with system size are called extensive. The entropy per degree of freedom is a system-specific constant. Many complex systems are nonextensive, meaning that if two initially insulated systems A and B, with multiplicities and , respectively, are brought into contact, the multiplicity of the combined system is . For such systems, which are typically strongly interacting, non-Markovian, or nonergodic, and the effective degrees of freedom do no longer scale as N. Given the appropriate scaling for , the entropy is a finite and nonzero constant in the thermodynamic limit, .A crucial observation in statistical mechanics is that the distribution of all macrostate variables gets sharply peaked and narrow as system size N increases. The reason behind this is that the multiplicities for particular macrostates grow much faster with N than those for other states. In the limit the probability of measuring a macrostate becomes a Dirac delta, which implies that one can replace the expectation value of a macrovariable by its most likely value. This is equivalent to maximizing the entropy in Eq. 1 with respect to the macrostate. By maximizing entropy one identifies the “typical” microconfigurations compatible with the macrostate. This typical region of phase space dominates all other possibilities and therefore characterizes the system. Probability distributions associated with these typical microconfigurations can be obtained in a constructive way by the maximum entropy principle (MEP), which is closely related to the question of finding the most likely distribution functions (histograms) for a given system.We demonstrate the MEP in the example of coin tossing. Consider a sequence of N independent outcomes of coin tosses, , where is either head or tail. The sequence x contains heads and tails. The probability of finding a sequence with exactly heads and tails iswhere is the binomial factor. We use the shorthand notation for the histogram of heads and tails and for the marginal probabilities for throwing head or tail. For the relative frequencies we write . We also refer to θ as the “biases” of the system. The probability of observing a particular sequence x with histogram k is given by . It is invariant under permutations of the sequence x because the coin tosses are independent. All possible sequences x with the same histogram k have identical probabilities. is the respective multiplicity, representing the number of possibilities to throw exactly heads and tails. As a consequence Eq. 2 becomes the probability of finding the distribution function p of relative frequencies for a given N. The MEP is used to find the most likely p. We denote the most likely histogram by and the most likely relative frequencies by .We now identify the two components that are necessary for the MEP to hold. The first is that in Eq. 2 factorizes into a multiplicity that depends on k only and a factor that depends on k and the biases θ. The second necessary component is that the multiplicity is related to an entropy expression. By using Stirling’s formula, the multiplicity of Eq. 2 can be trivially rewritten for large N,where an entropy functional of Shannon type (2) appears,The same arguments hold for multinomial processes with sequences x of N independent trials, where each trial takes one of W possible outcomes (3). In that case the probability for finding a given histogram k is is the multinomial factor and . Asymptotically holds. Extremizing Eq. 5 for fixed N with respect to k yields the most likely histogram, . Taking logarithms on both sides of Eq. 5 givesObviously, extremizing Eq. 6 leads to the same histogram . The term in Eq. 6 is sometimes called relative entropy or Kullback–Leibler divergence (4). We identify the first term on the right-hand side of Eq. 6 with Shannon entropy , and the second term is the so-called cross-entropy . Eq. 6 states that the cross-entropy is equal to entropy plus the relative entropy. The constraints of the MEP are related to the cross-entropy. For example, let the marginal probabilities be given by the so-called Boltzmann factor, , for the “energy levels” , where β is the inverse temperature and α the normalization constant. Inserting the Boltzmann factor into the cross-entropy, Eq. 6 becomeswhich is the MEP in its usual form, where Shannon entropy gets maximized under linear constraints. α and β are the Lagrangian multipliers for the normalization and the “energy” constraint , respectively. Note that in Eq. 6 we used to scale . Any other nonlinear would yield nonsensical results in the limit of , either 0 or ∞. Comparing with Eq. 1 shows that indeed, up to a constant multiplicative factor, . This means that the Boltzmann entropy per degree of freedom of a (uncorrelated) multinomial process is given by a Shannon-type entropy functional. Many systems that are nonergodic, are strongly correlated, or have long memory will not be of multinomial type, implying that is not invariant under permutations of a sequence x. For this situation it is not a priori evident that a factorization of into a θ-independent multiplicity and a θ-dependent term, as in Eq. 5, is possible. Under which conditions such a factorization is both feasible and meaningful is discussed in the next section.     

Generalized entropies and logarithms and their duality relations

For statistical systems that violate one of the four Shannon–Khinchin axioms, entropy takes a more general form than the Boltzmann–Gibbs entropy. The framework of superstatistics allows one to formulate a maximum entropy principle with these generalized entropies, making them useful for understanding distribution functions of non-Markovian or nonergodic complex systems. For such systems where the composability axiom is violated there exist only two ways to implement the maximum entropy principle, one using escort probabilities, the other not. The two ways are connected through a duality. Here we show that this duality fixes a unique escort probability, which allows us to derive a complete theory of the generalized logarithms that naturally arise from the violation of this axiom. We then show how the functional forms of these generalized logarithms are related to the asymptotic scaling behavior of the entropy.     

Testing the effects of FSHD candidate gene expression in vertebrate muscle development

The genetic lesion leading to facioscapulohumeral muscular dystrophy (FSHD) is a dominant deletion at the 4q35 locus. The generally accepted disease model involves an epigenetic dysregulation in the region resulting in the upregulation of one or more proximal genes whose overexpression specifically affects skeletal muscle. However, multiple FSHD candidate genes have been proposed without clear consensus. Using Xenopus laevis as a model for vertebrate development our lab has studied the effects of overexpression of the FSHD candidate gene ortholog, frg1 (FSHD region gene 1), showing that increased levels of frg1 systemically led specifically to an abnormal musculature and increased angiogenesis, the two most prominent clinical features of FSHD. Here we studied the overexpression effects of three other promising FSHD candidate genes, DUX4, DUX4c, and PITX1 using the same model system and methods for direct comparison. Expression of even very low levels of either DUX4 or pitx1 early in development led to massive cellular loss and severely abnormal development. These abnormalities were not muscle specific. In contrast, elevated levels of DUX4c resulted in no detectable adverse affects on muscle and DUX4c levels did not alter the expression of myogenic regulators. This data supports a model for DUX4 and PITX1 in FSHD only as pro-apoptotic factors if their expression in FSHD is confined to cells within the myogenic pathway; neither could account for the vascular pathology prevalent in FSHD. Taken together, increased frg1 expression alone leads to a phenotype that most closely resembles the pathophysiology observed in FSHD patients.     

Staged stent-assisted angioplasty for symptomatic intracranial vertebrobasilar artery stenosis

OBJECT: Medically refractory symptomatic vertebrobasilar atherosclerotic disease has a poor prognosis. Studies have shown that longer (> or = 10 mm), eccentric, high-grade (> 70%) stenoses portend increased procedure-related morbidity. The authors reviewed their experience to determine whether a staged procedure consisting of angioplasty followed by delayed (> or = 1 month later) repeated angioplasty and stent placement reduces the morbidity associated with endovascular treatment of symptomatic basilar and/or intracranial vertebral artery (VA) stenoses. METHODS: The authors retrospectively reviewed the medical records in a consecutive series of eight patients who underwent planned stent-assisted angioplasty for medically refractory, symptomatic atherosclerotic disease of the intracranial posterior circulation between February 1999 and January 2002. Staged stent-assisted angioplasty was planned for these patients because the extent and degree of stenosis of the VA and/or basilar artery (BA) lesion portended an excessive procedure-related risk. The degree of stenosis, recent onset of symptoms (unstable plaque), vessel tortuosity, and lesion length and morphological feaures were contributing factors in determining procedure-related risk. Patient records were analyzed for location and degree of stenosis, preprocedural regimen of antiplatelet and/or anticoagulation agents, devices used, procedure-related complications, and clinical and radiographic outcomes. Among the patients in whom staged stent-assisted angioplasty was planned, vessel dissection, which necessitated immediate stent placement, occurred during passage of the balloon in one of them. In a second patient, the stent could not be maneuvered through the tortuous VA. In a third patient, the VA and BAs remained widely patent after angioplasty alone, and therefore stent placement was not required. Significant complications among the eight patients included transient aphasia and hemiparesis in one and a groin hematoma that necessitated surgical intervention in another; there was no permanent neurological morbidity. The mean stenosis before treatment was 78%, which fell to 54% after angioplasty, and the mean residual stenosis after stent placement was 30%. At the last follow-up examination, none of the treated patients had further symptoms attributable to the treated stenosis. CONCLUSIONS: The novel combination of initial angioplasty followed by delayed endoluminal stent placement may reduce the neurological morbidity associated with endovascular treatment of long, high-grade stenotic lesions. Attempting to cross high-grade stenoses with higher-profile devices such as stents may result in an embolic shower. Furthermore, neointimal proliferation and scar formation after angioplasty result in a thickened fibrous layer, which may be protective during delayed stent deployment. Larger-scale studies involving multiple centers are needed to elucidate further the lesion morphological characteristics and patient population most likely to benefit from staged procedures.     

Primary pituitary abscess: case report

Pituitary abscesses are potentially life-threatening lesions if not appropriately diagnosed and treated. The authors have operated on more than five hundred cases of pituitary tumors and only one represented a case of pituitary abscess. A 35-year-old woman was investigated for chronic frontal headache. CT scan showed a cystic sellar lesion with ring enhancement after contrast injection leading to an initial diagnosis of pituitary adenoma. She underwent a sublabial transsphenoidal approach to the pituitary gland. After dural opening, purulent material was obtained and no tumor or other associated lesion was detected. There was no evidence of current or previous septicemic illness, meningitis, cavernous sinus thrombosis or sinus infection. Cultures were negative. She was put on antibiotics and discharged after 4 weeks. Nowadays, 10 years after treatment, she is doing well, with no anterior pituitary hormone deficit. MRI shows a partially empty sella without residual lesion and the pituitary stalck is in the midline. The early diagnosis and adequate treatment of this life-threatening lesion may result in excellent prognosis.     

Hindfoot containment orthosis for management of bone and soft-tissue defects of the heel

BACKGROUND: Bone, soft-tissue, and nerve deficits of the weightbearing surface of the foot are frequent sequelae from foot trauma or diabetes mellitus and present challenging treatment issues. Injury to the specialized, shock-absorbing, heel-pad tissue containing spirally arranged fat chambers is particularly difficult to manage. Appropriate footwear modifications and shoe inserts for protection of this skin are essential to the long-term management of bone and soft-tissue defects of the heel. This study evaluated the performance of a new custom total contact foot orthosis (Hindfoot Containment Orthosis, HCO) which was designed to contain the soft tissues of the heel, reduce shear forces, redistribute weightbearing load, and accommodate bone or soft-tissue deformity of the heel. METHODS: Twenty-two patients treated with HCO were retrospectively reviewed. Followup averaged 26 months. The effectiveness of the orthosis was assessed by how well the integrity of the soft tissue was maintained (e.g. the number of ulcerations since dispensing the orthosis), the number of refabrications of the orthosis that were required, and whether or not revision surgery was required. RESULTS: Ten patients had superficial ulcerations. No patient required revision surgery. A total of 62 refabrications of the orthoses in 22 patients were required over a 2-year period. Overall results were good in 17 (77%) patients, fair in four (18%), and poor in one. CONCLUSIONS: The HCO is effective for preservation of soft-tissue integrity of the heel pad after bony or soft-tissue injury. Important factors in achieving success with the HCO are patient compliance and periodic monitoring for refabrication of the orthosis to accommodate skeletal growth, change in foot size or shape, and compression or wear of insert materials.