Post-recurrence survival in hepatocellular carcinoma after percutaneous radiofrequency ablation

Background

Overall survival in hepatocellular carcinoma patients treated with percutaneous radiofrequency ablation is influenced by both recurrence and successive treatments. We investigated post-recurrence survival after radiofrequency ablation.

Methods

Data on 103 early/intermediate patients initially treated with radiofrequency ablation and followed for a median of 78 months (range 68–82) were retrospectively analysed. If intrahepatic disease recurrence occurred within or contiguous to the previously treated area it was defined as local, otherwise as distant; recurrence classified as Barcelona Clinic Liver Cancer stage C was defined by neoplastic portal vein thrombosis or metastases.

Results

A total of 103 patients were included (82.5% male; median age 70 years, range 39–86). During follow-up, 64 recurrences were observed. Median overall survival was 62 months (95% confidence interval: 54–78) and survival rates were 97%, 65% and 52% at 1, 4 and 5 years, respectively. Median post-recurrence survival was 22 months (95% confidence interval: 16–35). Child–Pugh score, performance status, sum of tumour diameters at recurrence and recurrence patterns were independent predictors of post-recurrence survival.

Conclusions

In patients with hepatocellular carcinoma after radiofrequency ablation, clinical and tumour parameters assessed at relapse, in particular the type of recurrence pattern, influence post-recurrence survival.     

Prefrontal Cortex Activated Bilaterally by a Tilt Board Balance Task: A Functional Near-Infrared Spectroscopy Study in a Semi-Immersive Virtual Reality Environment

The aim of this study was to assess the prefrontal cortex (PFC) oxygenation response to a 5-min incremental tilt board balance task (ITBBT) in a semi-immersive virtual reality (VR) environment driven by a depth-sensing camera. It was hypothesized that the PFC would be bilaterally activated in response to the increase of the ITBBT difficulty, given the PFC involvement in the allocation of the attentional resources to maintain postural control. Twenty-two healthy male subjects were asked to use medial–lateral postural sways to maintain their equilibrium on a virtual tilt board (VTB) balancing over a pivot. When the subject was unable to maintain the VTB angle within ±35° the VTB became red (error). An eight-channel fNIRS system was employed for measuring changes in PFC oxygenated-deoxygenated hemoglobin (O₂Hb-HHb, respectively). Results revealed that the number of the performed board sways and errors augmented with the increasing of the ITBBT difficulty. A PFC activation was observed with a tendency to plateau for both O₂Hb-HHb changes within the last 2 min of the task. A significant main effect of the level of difficulty was found in O₂Hb and HHb (p < 0.001). The study has demonstrated that the oxygenation increased over the PFC while the subject was performing an ITBBT in a semi-immersive VR environment. This increase was modulated by the task difficulty, suggesting that the PFC is bilaterally involved in attention-demanding tasks. This task could be considered useful for diagnostic testing and functional neurorehabilitation given its adaptability in elderly and in patients with movement disorders.     

IsdC from Staphylococcus lugdunensis Induces Biofilm Formation under Low-Iron Growth Conditions

Staphylococcus lugdunensis is a coagulase-negative staphylococcus that is a commensal of humans and an opportunistic pathogen. It can cause a spectrum of infections, including those that are associated with the ability to form biofilm, such as occurs with endocarditis or indwelling medical devices. The genome sequences of two strains revealed the presence of orthologues of the ica genes that are responsible for synthesis of poly-N-acetylglucosamine (PNAG) that is commonly associated with biofilm in other staphylococci. However, we discovered that biofilm formed by a panel of S. lugdunensis isolates growing in iron-restricted medium was susceptible to degradation by proteases and not by metaperiodate, suggesting that the biofilm matrix comprised proteins and not PNAG. When the iron concentration was raised to 1 mM biofilm formation by all strains tested was greatly reduced. A mutant of strain N920143 lacking the entire locus that encodes iron-regulated surface determinant (Isd) proteins was defective in biofilm formation under iron-limited conditions. An IsdC-null mutant was defective, whereas IsdK, IsdJ, and IsdB mutants formed biofilm to the same level as the parental strain. Expression of IsdC was required both for the primary attachment to unconditioned polystyrene and for the accumulation phase of biofilm involving cell-cell interactions. Purified recombinant IsdC protein formed dimers in solution and Lactococcus lactis cells expressing only IsdC adhered to immobilized recombinant IsdC but not to IsdJ, IsdK, or IsdB. This is consistent with a specific homophilic interaction between IsdC molecules on neighboring cells contributing to accumulation of S. lugdunensis biofilm in vivo.     

Balanced and unbalanced solutions modulate the release of Matrix Metalloproteinase-9 (MMP-9) from neutrophils in response to inflammatory stimuli: an in vitro study

Objectives and design

We investigated the effect of balanced (BS) and unbalanced (UBS) solutions in the absence or presence of hydroxyethyl starch (HES) on neutrophil functionality, evaluating the release of matrix metalloproteinase (MMP)-9, myeloperoxidase (MPO), and MMP-8.

Materials and methods

Neutrophils were isolated by gradient centrifugation and dextran sedimentation and incubated in BS or UBS without or with HES, in the absence or presence of Interleukin-8 (IL-8) or Lipopolysaccharide (LPS). MMP-9, MPO, and MMP-8 were assayed by commercially available ELISA kits.

Results

There was not any influence of volume replacement solutions on the release of the enzymes from resting neutrophils. After IL-8 stimulation, the release of MMP-9 was higher in BS than in UBS or RPMI-1640, whereas HES enhanced its release regardless of the composition. After LPS stimulation, the release of MMP-9 was higher in both UBS and BS than RPMI-1640, but HES brought its release back to physiological conditions. No difference was found in the release of MPO and MMP-8 after stimulation with IL-8 or LPS.

Conclusion

Volume replacement solutions might have an impact on the release of MMP-9 depending on the inflammatory milieu, suggesting that the use of balanced or unbalanced solutions is not a neutral choice.     

Classification of Lower Extremity Movement Patterns Based on Visual Assessment: Reliability and Correlation With 2-Dimensional Video Analysis

Context:

Abnormal movement patterns have been implicated in lower extremity injury. Reliable, valid, and easily implemented assessment methods are needed to examine existing musculoskeletal disorders and investigate predictive factors for lower extremity injury.

Objective:

To determine the reliability of experienced and novice testers in making visual assessments of lower extremity movement patterns and to characterize the construct validity of the visual assessments.

Design:

Cross-sectional study.

Setting:

University athletic department and research laboratory.

Patients or Other Participants:

Convenience sample of 30 undergraduate and graduate students who regularly participate in athletics (age = 19.3 ± 4.5 years). Testers were 2 experienced physical therapists and 1 novice postdoctoral fellow (nonclinician).

Main Outcome Measure(s):

We took videos of 30 athletes performing the single-legged squat. Three testers observed the videos on 2 occasions and classified the lower extremity movement as dynamic valgus, no change, or dynamic varus. The classification was based on the estimated change in frontal-plane projection angle (FPPA) of the knee from single-legged stance to maximum single-legged squat depth. The actual FPPA change was measured quantitatively. We used percentage agreement and weighted κ to examine tester reliability and to determine construct validity of the visual assessment.

Results:

The κ values for intratester and intertester reliability ranged from 0.75 to 0.90, indicating substantial to excellent reliability. Percentage agreement between the visual assessment and the quantitative FPPA change category was 90%, with a κ value of 0.85.

Conclusions:

Visual assessments were made reliably by experienced and novice testers. Additionally, movement-pattern categories based on visual assessments were in excellent agreement with objective methods to measure FPPA change. Therefore, visual assessments can be used in the clinic to assess movement patterns associated with musculoskeletal disorders and in large epidemiologic studies to assess the association between lower extremity movement patterns and musculoskeletal injury.Key Words: movement analysis, screening, athletic injuries, knee valgus

Key Points

• With training and the use of standardized techniques, both experienced and novice testers reliably classified lower extremity movement patterns based on visual assessment.
• Movement-pattern category-based visual assessments were in excellent agreement with objective methods to measure changes in frontal-plane projection angle.
• Visual assessment based on the methods described in this study may be used in the clinical setting, as well as in large epidemiologic studies and screening assessments for sport participation, to identify distinct categories of lower extremity movement patterns.

Abnormal movement patterns of the lower extremity have been implicated in noncontact anterior cruciate ligament (ACL) injuries¹ and other musculoskeletal problems, such as patellofemoral pain^2–4 and acetabular labral tears.⁵ In addition, correcting these abnormal movement patterns has been shown to prevent ACL injury⁶ and is proposed to reduce symptoms in people with preexisting pain conditions.^5,7,8 Thus, assessment of lower extremity movement patterns may be a way to guide treatment of existing musculoskeletal pain problems and to identify people at risk for future injury or musculoskeletal pain. To facilitate the examination of existing musculoskeletal disorders and the investigation of predictive factors of lower extremity injury, reliable, valid, and feasible methods to assess lower extremity movement patterns are needed.One method to assess lower extremity movement patterns is the Landing Error Scoring System (LESS).^9–11 The LESS uses a standard technique to make visual assessments of movement patterns during a drop vertical jump. The LESS is reliable and valid^9–11; however, the drop vertical jump is a relatively high-level activity and may not be the best way to assess movement patterns in patients with existing injury or in athletes whose sports do not involve landing from a jump. In addition, the drop vertical jump is a bilateral activity that may allow the participant to use 1 limb to compensate for the other. Visual assessment of the single-legged squat (SLSquat), a unilateral limb task, may provide an alternative to the LESS.We have developed standardized methods using a visual assessment of the frontal-plane projection angle (FPPA) to classify the lower extremity movement pattern during an SLSquat. The FPPA is a 2-dimensional (2-D) representation of the lower extremity position¹² and has been used to identify differences between men and women¹² and between women with patellofemoral pain and control participants^4,13 and to detect change in movement patterns after specific training.¹⁴ We established specific criteria to define the categories of lower extremity movement pattern based on the change in FPPA (FPPA change) during motion. The tester observes the angle formed between a line that bisects the thigh and a line that bisects the lower leg. During movement tests, the tester compares the FPPA at the start position with the FPPA at the end position. For example, to assess an SLSquat, the examiner compares the FPPA during the start position of single-legged stance with the end position of maximum squat depth. The difference observed in FPPA from the start to the end position can then be classified as dynamic valgus (change in the valgus direction), no change, or dynamic varus (change in the varus direction). We have used this assessment extensively in the clinical setting, but we have not assessed the rater reliability or the construct validity of our visual assessments.The purpose of this study was to assess the intratester and intertester reliability of 3 testers (2 experienced, 1 novice) categorizing the lower extremity movement pattern demonstrated during an SLSquat. A standardized protocol was used to assess videos of healthy participants performing the SLSquat. We hypothesized that the testers, both experienced and novice, would demonstrate good to excellent reliability using the standardized methods. In addition, we used the objective measure of quantifying FPPA as described by Willson and Davis¹² to determine the construct validity of our visual assessments. We hypothesized that we would see good to excellent agreement between our visual assessments and the quantitative FPPA change.     

Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease

Defective mitochondrial distribution in neurons is proposed to cause ATP depletion and calcium-buffering deficiencies that compromise cell function. However, it is unclear whether aberrant mitochondrial motility and distribution alone are sufficient to cause neurological disease. Calcium-binding mitochondrial Rho (Miro) GTPases attach mitochondria to motor proteins for anterograde and retrograde transport in neurons. Using two new KO mouse models, we demonstrate that Miro1 is essential for development of cranial motor nuclei required for respiratory control and maintenance of upper motor neurons required for ambulation. Neuron-specific loss of Miro1 causes depletion of mitochondria from corticospinal tract axons and progressive neurological deficits mirroring human upper motor neuron disease. Although Miro1-deficient neurons exhibit defects in retrograde axonal mitochondrial transport, mitochondrial respiratory function continues. Moreover, Miro1 is not essential for calcium-mediated inhibition of mitochondrial movement or mitochondrial calcium buffering. Our findings indicate that defects in mitochondrial motility and distribution are sufficient to cause neurological disease.Motor neuron diseases (MNDs), including ALS and spastic paraplegia (SP), are characterized by the progressive, length-dependent degeneration of motor neurons, leading to muscle atrophy, paralysis, and, in some cases, premature death. There are both inherited and sporadic forms of MNDs, which can affect upper motor neurons, lower motor neurons, or both. Although the molecular and cellular causes of most MNDs are unknown, many are associated with defects in axonal transport of cellular components required for neuron function and maintenance (1–6).A subset of MNDs is associated with impaired mitochondrial respiration and mitochondrial distribution. This observation has led to the hypothesis that neurodegeneration results from defects in mitochondrial motility and distribution, which, in turn, cause subcellular ATP depletion and interfere with mitochondrial calcium ([Ca²⁺]_m) buffering at sites of high synaptic activity (reviewed in ref. 7). It is not known, however, whether mitochondrial motility defects are a primary cause or a secondary consequence of MND progression. In addition, it has been difficult to isolate the primary effect of mitochondrial motility defects in MNDs because most mutations that impair mitochondrial motility in neurons also affect transport of other organelles and vesicles (1, 8–11).In mammals, the movement of neuronal mitochondria between the cell body and the synapse is controlled by adaptors called trafficking kinesin proteins (Trak1 and Trak2) and molecular motors (kinesin heavy chain and dynein), which transport the organelle in the anterograde or retrograde direction along axonal microtubule tracks (7, 12–24). Mitochondrial Rho (Miro) GTPase proteins are critical for transport because they are the only known surface receptors that attach mitochondria to these adaptors and motors (12–15, 18, 25, 26). Miro proteins are tail-anchored in the outer mitochondrial membrane with two GTPase domains and two predicted calcium-binding embryonic fibroblast (EF) hand motifs facing the cytoplasm (12, 13, 25, 27, 28). A recent Miro structure revealed two additional EF hands that were not predicted from the primary sequence (29). Studies in cultured cells suggest that Miro proteins also function as calcium sensors (via their EF hands) to regulate kinesin-mediated mitochondrial “stopping” in axons (15, 16, 26). Miro-mediated movement appears to be inhibited when cytoplasmic calcium is elevated in active synapses, effectively recruiting mitochondria to regions where calcium buffering and energy are needed. Despite this progress, the physiological relevance of these findings has not yet been tested in a mammalian animal model. In addition, mammals ubiquitously express two Miro orthologs, Miro1 and Miro2, which are 60% identical (12, 13). However, the individual roles of Miro1 and Miro2 in neuronal development, maintenance, and survival have no been evaluated.We describe two new mouse models that establish the importance of Miro1-mediated mitochondrial motility and distribution in mammalian neuronal function and maintenance. We show that Miro1 is essential for development/maintenance of specific cranial neurons, function of postmitotic motor neurons, and retrograde mitochondrial motility in axons. Loss of Miro1-directed retrograde mitochondrial transport is sufficient to cause MND phenotypes in mice without abrogating mitochondrial respiratory function. Furthermore, Miro1 is not essential for calcium-mediated inhibition of mitochondrial movement or [Ca²⁺]_m buffering. These findings have an impact on current models for Miro1 function and introduce a specific and rapidly progressing mouse model for MND.     

Community Health Workers and Stand-Alone or Integrated Case Management of Malaria: A Systematic Literature Review

A systematic literature review was conducted to assess the effectiveness of strategies to improve community case management (CCM) of malaria. Forty-three studies were included; most (38) reported indicators of community health worker (CHW) performance, 14 reported on malaria CCM integrated with other child health interventions, 16 reported on health system capacity, and 13 reported on referral. The CHWs are able to provide good quality malaria care, including performing procedures such as rapid diagnostic tests. Appropriate training, clear guidelines, and regular supportive supervision are important facilitating factors. Crucial to sustainable success of CHW programs is strengthening health system capacity to support commodity supply, supervision, and appropriate treatment of referred cases. The little evidence available on referral from community to health facility level suggests that this is an area that needs priority attention. The studies of integrated CCM suggest that additional tasks do not reduce the quality of malaria CCM provided sufficient training and supervision is maintained.