Phosphate signaling through alternate conformations of the PstSCAB phosphate transporter.

BACKGROUND: Phosphate is an essential compound for life. Escherichia coli employs a signal transduction pathway that controls the expression of genes that are required for the high-affinity acquisition of phosphate and the utilization of alternate sources of phosphorous. These genes are only expressed when environmental phosphate is limiting. The seven genes for this signaling pathway encode the two-component regulatory proteins PhoB and PhoR, as well as the high-affinity phosphate transporter PstSCAB and an auxiliary protein called PhoU. As the sensor kinase PhoR has no periplasmic sensory domain, the mechanism by which these cells sense environmental phosphate is not known. This paper explores the hypothesis that it is the alternating conformations of the PstSCAB transporter which are formed as part of the normal phosphate transport cycle that signal phosphate sufficiency or phosphate limitation. RESULTS: We tested two variants of PstB that are predicted to lock the protein in either of two conformations for their signaling output. We observed that the pstBQ160K mutant, predicted to reside in an inward-facing, open conformation signaled phosphate sufficiency whereas the pstBE179Q mutant, predicted to reside in an outward-facing, closed conformation signaled phosphate starvation. Neither mutant showed phosphate transport. CONCLUSIONS: These results support the hypothesis that the alternating conformations of the PstSCAB transporter are sensed by PhoR and PhoU. This sensory mechanism thus controls the alternate autokinase and phospho-PhoB phosphatase activities of PhoR, which ultimately control the signaling state of the response regulator PhoB.

Evidence for the Validation of a Single Item Recovery Question (SIRQ) in Children With Mild and Complicated Mild Traumatic Brain Injury.

BACKGROUND: Recovery from a brain injury occurs in varying degrees. The objective of this study was to investigate the concurrent validity of a parent-reported 10-point scale for degree of recovery, Single Item Recovery Question (SIRQ), in children with mild traumatic brain injury (mTBI) or complicated mTBI (C-mTBI) compared with validated assessments of symptom burden (Post-Concussion Symptom Inventory Parent form-PCSI-P) and quality of life (Pediatric Quality of Life Inventory [PedsQL]). METHODS: A survey was sent to parents of children aged five to 18 years who presented to pediatric level I trauma center with mTBI or C-mTBI. Data included parent-reported postinjury recovery and functioning of children. Pearson correlation coefficients (r) were calculated to measure the associations of the SIRQ with the PCSI-P and the PedsQL. Hierarchical linear regression models were used to examine if covariates would increase the predictive value of the SIRQ to the PCSI-P and the PedsQL total scores. RESULTS: Of 285 responses (175 mTBI and 110 C-mTBI) analyzed, Pearson correlation coefficients for the SIRQ to the PCSI-P (r = -0.65, P < 0.001) and PedsQL total and subscale scores were all significant (P < 0.001) with mostly large-sized effects (r ≥ 0.500), regardless of mTBI classification. Covariates, including mTBI classification, age, gender, and years since injury, resulted in minimum changes in the predictive value of the SIRQ to the PCSI-P and the PedsQL total scores. CONCLUSIONS: The findings demonstrate preliminary evidence for the concurrent validity of the SIRQ in pediatric mTBI and C-mTBI.

Sensory Phenotypes for Balance Dysfunction After Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: Recent team-based models of care use symptom subtypes to guide treatments for individuals with chronic effects of mild traumatic brain injury (mTBI). However, these subtypes, or phenotypes, may be too broad, particularly for balance (e.g., 'vestibular subtype'). To gain insight into mTBI-related imbalance we 1) explored whether a dominant sensory phenotype (e.g., vestibular impaired) exists in the chronic mTBI population, 2) determined the clinical characteristics, symptomatic clusters, functional measures, and injury mechanisms that associate with sensory phenotypes for balance control in this population, and 3) compared the presentations of sensory phenotypes between individuals with and without previous mTBI. METHODS: A secondary analysis was conducted on the Long-Term Impact of Military-Relevant Brain Injury Consortium - Chronic Effects of Neurotrauma Consortium. Sensory ratios were calculated from the Sensory Organization Test, and individuals were categorized into one of eight possible sensory phenotypes. Demographic, clinical, and injury characteristics were compared across phenotypes. Symptoms, cognition, and physical function were compared across phenotypes, groups, and their interaction. RESULTS: Data from 758 Service Members and Veterans with mTBI and 172 with no lifetime history of mTBI were included. Abnormal visual, vestibular, and proprioception ratios were observed in 29%, 36%, and 38% of people with mTBI, respectively, with 32% exhibiting more than one abnormal sensory ratio. Within the mTBI group, global outcomes (p<0.001), self-reported symptom severity (p<0.027), and nearly all physical and cognitive functioning tests (p<0.027) differed across sensory phenotypes. Individuals with mTBI generally reported worse symptoms than their non-mTBI counterparts within the same phenotype (p=0.026), but participants with mTBI in the Vestibular-Deficient phenotype reported lower symptom burdens than their non-mTBI counterparts [e.g., mean(SD) Dizziness Handicap Inventory = 4.9(8.1) for mTBI vs. 12.8(12.4) for non-mTBI, group*phenotype interaction p<0.001]. Physical and cognitive functioning did not differ between groups after accounting for phenotype. DISCUSSION: Individuals with mTBI exhibit a variety of chronic balance deficits involving heterogeneous sensory integration problems. While imbalance when relying on vestibular information is common, it is inaccurate to label all mTBI-related balance dysfunction under the 'vestibular' umbrella. Future work should consider specific classification of balance deficits, including specific sensory phenotypes for balance control.

Hyperhidrosis of the residual limb: a narrative review of the measurement and treatment of excess perspiration affecting individuals with amputation.

BACKGROUND: Hyperhidrosis (HH) is a relatively common disorder involving excessive sweating, typically of the palms or axilla. HH can also frequently occur after limb amputation, where the remaining residual limb excessively perspires, leading to an increased risk of dermatological disorders and functional limitations, such as the inability to comfortably or safely wear a prosthesis. Although many treatments have been proposed to treat HH within the dermatology community, they are not widely known by healthcare providers typically involved in caring for individuals with acquired limb loss. OBJECTIVES: To appraise the current state of quantitative and qualitative assessment of HH within the residual limb and examine existing and future treatment strategies for this problem. STUDY DESIGN: Narrative Literature Review. METHODS: A literature review focused on the assessment and treatment of excessive sweating of residual limbs. RESULTS: There is currently no objective or subjective standard to assess or diagnose HH of the residual limb. Conventional therapies for HH do not always translate to the population of individuals with limb loss. Emerging modalities for treating HH show promise toward a permanent resolution of excess perspiration but require additional studies within people with amputation. CONCLUSIONS: Further research is needed to quantify standard values to objectively and subjectively assess and diagnose hyperhidrosis of the residual limb. New and developing treatments for hyperhidrosis require additional studies to assess efficacy and safety in the residual limb.

Prolonged, severe intrathecal baclofen withdrawal syndrome: a case report.

Intrathecal baclofen (ITB) withdrawal is a well-recognized complication when drug delivery is disrupted for any reason. ITB withdrawal varies widely in its severity and poses the very real possibility of death if not promptly managed. Cases of withdrawal lasting greater than 1 or 2 weeks, however, are sparse. We report the case of an 11-year-old girl with spastic quadriplegic cerebral palsy who developed an infected pump and subsequent meningitis, prompting the removal of her pump and catheter. She subsequently developed a severe, prolonged baclofen withdrawal syndrome marked by increased spasticity, agitation, hypertension, and tachycardia that lasted nearly 2 months, requiring intensive care and continuous intravenous sedation with benzodiazepines and opiates. Her pump was eventually replaced on hospital day 56 and within 24 hours her symptoms dramatically improved. She was eventually weaned off sedating medications and returned to baseline functional status. Typical management of baclofen withdrawal is reviewed. To date, the literature has not discussed the potential role for opiates in managing baclofen withdrawal, yet a growing body of literature is examining the interplay between opiates and gamma-aminobutyric acid B pathways. A potential role for opiates in managing severe baclofen withdrawal is proposed.

Residual Limb Hyperhidrosis Managed by Botulinum Toxin Injections, Enhanced by the Iodine-Starch Test: A Case Report.

Hyperhidrosis of the residual limb is a common condition affecting patients with amputations. The iodine-starch test is used by dermatologists to identify focal areas of hyperhidrosis before treatment with botulinum toxin. Here, we describe a case of a patient with a transtibial amputation with moderate-to-severe hyperhidrosis who received intradermal botulinum toxin injections to treat residual limb hyperhidrosis, with particular emphasis given to the utility of the iodine-starch test in managing this common condition. The iodine-starch test successfully identified hyperhidrotic areas before treatment as well as confirmed the physiologic anhidrotic effect of the botulinum toxin treatment. LEVEL OF EVIDENCE: V.