Clinical diagnoses of patients showing caloric inversion

Abstract Objectives When air irrigation is used for caloric stimulation in patients with a perforated ear, warm irrigation may elicit a nystagmus that initially beats in the opposite direction of what is expected for warm irrigations, which is referred to as "caloric inversion". This study aimed to investigate the disease group in which caloric inversion appeared in patients who underwent caloric testing and to classify the patterns of caloric inversion. Methods We conducted a retrospective review of bithermal caloric test results that were collected in our dizziness clinic between 2005 and 2022. Caloric inversion was defined when nystagmus induced by caloric stimulation appeared in the opposite direction to that expected. The incidence of caloric inversion among all patients who underwent bithermal caloric tests was calculated. To confirm the clinical diagnoses of the patients with caloric inversion, their clinical records were reviewed. Results Out of 9923 patients who underwent bithermal caloric tests, 29 patients (0.29%) showed a caloric inversion. The most common clinical diagnosis was chronic otitis media (21 of 29, 72%). Of the 21 patients with chronic otitis media, 20 patients showed a caloric inversion by warm air irrigation and one patient showed caloric inversion by cold air stimulation. Patients with clinical diagnoses other than chronic otitis media such as sudden sensorineural hearing loss, benign paroxysmal vertigo of childhood and recurrent vestibulopathy showed caloric inversion by warm air irrigation. Caloric inversion by warm water irrigation was observed in patients with lateral semicircular canal cupulopathy and recurrent vestibulopathy. Two patients (one with Meniere's disease and one with age-related dizziness) showed caloric inversion by cold water irrigation. Conclusion Caloric inversion can be observed in various diseases other than chronic otitis media with tympanic membrane perforation. Special care should be taken in the interpretation of caloric test results. Level of Evidence: Level 4.

Cerebellopontine angle tumor presenting as acute audiovestibular syndrome.

BACKGROUND: Acute audiovestibular deficits may be a harbinger of vestibular schwannoma (VS). OBJECTIVE: To investigate clinical and laboratory features of 25 consecutive patients with VS presenting with acute audiovestibular deficits. METHODS: A symptomatic combination of acute audiovestibular deficits was investigated. Audiometric and vestibular function tests, and internal auditory canal magnetic resonance imaging (IAC MRI) results were evaluated. RESULTS: Varying combinations of symptoms may develop in VS patients with acute audiovestibular deficits, of whom sudden hearing loss (HL) without acute vertigo or acute facial nerve palsy (FNP) was most common. The most common audiometric configuration was high-tone hearing loss, and no patient showed low-tone hearing loss. IAC MRI demonstrated that the tumor had an intracanalicular portion and attachment to the bony IAC wall in all patients and widened the IAC wall in some patients. CONCLUSION: Different symptomatic combinations of acute audiovestibular deficits may develop in patients with VS. Awareness about the possibility of VS as a cause of sudden HL, acute vertigo, and acute FNP, as well as subsequent IAC MRI scanning is vital to earlier diagnosis of VS in these patients.

All-Cause and Cause-Specific Mortality Attributable to Seasonal Influenza: A Nationwide Matched Cohort Study.

BACKGROUND: Although influenza poses substantial mortality burden, most studies have estimated excess mortality using time-aggregated data. Here, we estimated mortality risk and population attributable fraction (PAF) attributed to seasonal influenza using individual-level data from a nationwide matched cohort. METHODS: Individuals with influenza during four consecutive influenza seasons (2013-2017) (n = 5,497,812) and 1:4 age- and sex-matched individuals without influenza (n = 20,990,683) were identified from a national health insurance database. The endpoint was mortality within 30 days after influenza diagnosis. All-cause and cause-specific mortality risk ratios (RRs) attributed to influenza were estimated. Excess mortality, mortality RR, and PAF of mortality were determined, including for underlying disease subgroups. RESULTS: Excess mortality rate, mortality RR, and PAF of all-cause mortality were 49.5 per 100,000, 4.03 (95% confidence interval [CI], 3.63-4.48), and 5.6% (95% CI, 4.5-6.7%). Cause-specific mortality RR (12.85; 95% CI, 9.40-17.55) and PAF (20.7%; 95% CI, 13.2-27.0%) were highest for respiratory diseases. In subgroup analysis according to underlying disorders, PAF of all-cause mortality was 5.9% (95% CI, 0.6-10.7%) for liver disease, 5.8% (95% CI, 2.9-8.5%) for respiratory disease, and 3.8% (95% CI, 1.4-6.1%) for cancer. CONCLUSION: Individuals with influenza had a 4-fold higher mortality risk than individuals without influenza. Preventing seasonal influenza may lead to 5.6% and 20.7% reductions in all-cause and respiratory mortality, respectively. Individuals with respiratory disease, liver disease, and cancer may benefit from prioritization when establishing influenza prevention strategies.

Spontaneous Nystagmus in Patients With Posterior Semicircular Canal Benign Paroxysmal Positional Vertigo.

OBJECTIVE: This study aimed to investigate the incidence of spontaneous nystagmus (SN) in posterior semicircular canal (PSCC) benign paroxysmal positional vertigo (BPPV) and its effect on treatment outcomes. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. METHODS: This study included 50 patients with idiopathic unilateral PSCC BPPV between July 2021 and May 2022. The presence of SN was investigated, and the results of the bithermal caloric test and video head impulse test (vHIT) were compared. RESULTS: SN was observed in 13 (26%) of the 50 patients presenting PSCC BPPV. The direction of SN was mainly unidirectional and horizontal in 12 of the 13 patients with a slow-phase velocity ranging from 2 to 4°/s. One patient presented an upbeating torsional SN at the initial evaluation. The mean vHIT gain of the PSCC on the affected side was significantly lower in patients with SN than those without SN (p = .004, Mann-Whitney U test). The proportion of patients who recovered within 2 sessions of the repositioning maneuver was significantly higher in those without SN than that in those with SN (p < .001, Fisher's exact test). CONCLUSION: This study demonstrated that the treatment outcomes of PSCC BPPV were significantly worse in patients with SN than those without SN. Examining the presence of SN in patients with PSCC BPPV may be helpful in counseling the patients on prognosis, and it is expected that more sessions of canalith repositioning maneuver may be required to treat PSCC BPPV in patients with SN than those without SN.

Objective measurement of HINTS (Head Impulse, Nystagmus, Test of Skew) in peripheral vestibulopathy.

OBJECTIVE: To evaluate how often the positive sign of HINTS (Head-Impulse, Gaze Evoked Nystagmus, Test of Skew) appears in patients with acute peripheral vestibular lesion, HINTS findings were quantitatively measured and analyzed in patients with peripheral vestibulopathy accompanying spontaneous nystagmus. METHODS: HINTS was evaluated in 14 vertigo patients with spontaneous nystagmus. Horizontal vestibulo-ocular reflex (VOR) gain was measured using the video head impulse test (vHIT). To evaluate gaze-evoked nystagmus (GEN), slow-phase velocities at different points of lateral gaze were measured and plotted, then the slope and its inverse value, the neural integrator time constant, were calculated. Skew deviation was tested using anaglyph filters to simulate the alternate cover test, and the degree and latency of vertical eyeball deviation were measured. The ABCD2 score was calculated to evaluate the risk of stroke. RESULTS: Among 13 patients of peripheral vestibulopathy, 7 showed positive signs in HINTS (normal vHIT: 5, direction-changing GEN: 0, skew deviation: 3). One patient with a cerebellopontine angle tumor presented with both a peripheral and central pattern and showed positive HINTS findings (presence of direction-changing GEN). The mean VOR gain of patients with abnormal vHIT was 0.58±0.29 and 1.10±0.11 in the affected and contralateral side, respectively, while those in patients with normal vHIT were 1.04±0.21 and 1.13±0.12, respectively. The neural integrator time constant calculated from the mean slope of horizontal slow-phase velocity according to horizontal eye position was 42.9 s. The mean vertical eyeball deviation of patients with positive skew was 2.14±1.18° while uncovering the eye on the affected side, and -1.97±1.59° while uncovering the eye on the unaffected side. The median ABCD2 score of 14 patients was 2 (range, 1-3). CONCLUSIONS: HINTS findings were objectively measured in vertigo patients with spontaneous nystagmus. Although positive findings of HINTS have been recognized as a central sign, 54% (7/13) of cases with peripheral vestibulopathy showed positive HINTS signs. HINTS results should be interpreted carefully considering that a substantial proportion of peripheral vestibulopathy shows a positive HINTS sign.

Tympanic Membrane Perforation After Intratympanic Steroid Injection: A Systematic Review and Meta-analysis.

OBJECTIVE: We investigated the incidence of tympanic membrane (TM) perforations induced after intratympanic steroid injection (ITSI) in patients with sudden sensorineural hearing loss (SSNHL) through a systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, and MEDLINE. REVIEW METHODS: Primary database searches were performed, and 1901 records were identified. After removal of 1802 articles through abstract screening, the remaining 99 full-text journals were assessed for eligibility to be included in the study. Fifty-eight studies that used either ventilation tubing (VT) or tympanocentesis (TC) for ITSI were selected for analysis. The subjects were divided into VT and TC groups. The rate of TM perforation after ITSI in 2 groups, sites of ITSI, needle gauge, and influence on residual hearing were investigated. RESULTS: The cohorts comprised patients who underwent VT (n = 257, 9.6%) and TC (n = 2415, 90.4%). The proportion of TM perforation after ITSI in each group was 0.073 (95% CI, 0.0469-0.1113) and 0.010 (95% CI, 0.0045-0.0215), respectively, which suggested that the VT group showed a significantly higher TM perforation rate than the TC group (P < .001). In the subgroup analyses, there was no significant difference in the odds ratio for the rate of TM perforation according to the injection site and needle gauge for TC. The proportion of surgical repair showed no significant difference between the 2 groups. CONCLUSION: ITSI via VT may have a significantly higher risk of TM perforation than ITSI via TC, although those are relatively small overall. ITSI should be performed in the direction to minimize possible adverse effects.

Direction-changing spontaneous nystagmus in cerebellopontine angle tumour.

The most common symptoms of tumours involving the cerebellopontine angle (CPA) are unilateral sensorineural hearing loss, dizziness, and asymmetric tinnitus. While the clinical manifestations have been well documented in previous studies, the nystagmus findings in these patients have not been thoroughly investigated yet. This study aimed to investigate the incidence of direction-changing spontaneous nystagmus in patients with CPA tumours, evaluate their radiologic characteristics, and gain insight into the mechanisms underlying nystagmus. Direction-changing spontaneous nystagmus was observed in 6 out of 83 patients (7%) with CPA tumours during the 7-year period. Temporal bone magnetic resonance imaging findings revealed the presence of an intrameatal mass in CPA tumours in all six patients with direction-changing spontaneous nystagmus. Vestibular schwannomas were confined within the internal auditory meatus in four patients, and petroclival meningiomas extended into the internal auditory meatus in two patients. The mechanism of direction-changing spontaneous nystagmus may be explained as paroxysmal secondary central hyperactivity in the vestibular nucleus due to the long-standing pressure effect in the vestibular nerve by tumours, or by ephaptic discharges in the vestibular nerve.

A DNA-derived phage nose using machine learning and artificial neural processing for diagnosing lung cancer.

There is a growing interest in electronic nose-based diagnostic systems that are fast and portable. However, existing technologies are suitable only for operation in the laboratory, making them difficult to apply in a rapid, non-face-to-face, and field-suitable manner. Here, we demonstrate a DNA-derived phage nose (D2pNose) as a portable respiratory disease diagnosis system requiring no pretreatment. D2pNose was produced based on phage colour films implanted with DNA sequences from mammalian olfactory receptor cells, and as a result, it possesses the comprehensive reactivity of these cells. The manipulated surface chemistry of the genetically engineered phages was verified through a correlation analysis between the calculated and the experimentally measured reactivity. Breaths from 31 healthy subjects and 31 lung cancer patients were collected and exposed to D2pNose without pretreatment. With the help of deep learning and neural pattern separation, D2pNose has achieved a diagnostic success rate of over 75% and a classification success rate of over 86% for lung cancer based on raw human breath. Based on these results, D2pNose can be expected to be directly applicable to other respiratory diseases.

A screen of FDA-approved drugs identifies inhibitors of protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3).

Protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3) is highly expressed in a variety of cancers, where it promotes tumor cell migration and metastasis leading to poor prognosis. Despite its clinical significance, small molecule inhibitors of PRL-3 are lacking. Here, we screened 1443 FDA-approved drugs for their ability to inhibit the activity of the PRL phosphatase family. We identified five specific inhibitors for PRL-3 as well as one selective inhibitor of PRL-2. Additionally, we found nine drugs that broadly and significantly suppressed PRL activity. Two of these broad-spectrum PRL inhibitors, Salirasib and Candesartan, blocked PRL-3-induced migration in human embryonic kidney cells with no impact on cell viability. Both drugs prevented migration of human colorectal cancer cells in a PRL-3 dependent manner and were selective towards PRLs over other phosphatases. In silico modeling revealed that Salirasib binds a putative allosteric site near the WPD loop of PRL-3, while Candesartan binds a potentially novel targetable site adjacent to the CX5R motif. Inhibitor binding at either of these sites is predicted to trap PRL-3 in a closed conformation, preventing substrate binding and inhibiting function.

Outcome of Cochlear Implantation in NLRP3-related Autoinflammatory Inner Ear Disorders.

OBJECTIVE: Hearing loss is a highly penetrant phenotype in NLRP3 (Nod-Like-Receptor-Pyrin containing 3) gene-related autoinflammatory disorders. A recent study revealed potential medical treatment of hearing loss with anakinra (anti-interleukin 1 receptor antagonist) in selected cases. However, for severely aggravated hearing loss not responsive to anakinra, cochlear implantation (CI) would be the last resort for hearing rehabilitation. Outcome of CI is not clearly elucidated yet in this emerging type of hearing loss related to NLRP3-related autoinflammatory disorders, which has a systemic nature and ubiquitous distribution of resident macrophages involving the spiral ganglion neuron and the cochlear nerve. Here, we report the successful outcome of CI in NLRP3-related autoinflammatory disorder. PATIENTS: Three subjects representing each type of NLRP3-related autoinflammatory disorder: chronic infantile, neurological, cutaneous, and articular syndrome; Muckle-Wells syndrome; and DFNA34, who underwent CI for auditory rehabilitation, were recruited. INTERVENTIONS: Phenotypes as well as genotypes were reviewed in the subjects. MAIN OUTCOME MEASURES: Audiologic performances before/after CI over time were evaluated. RESULTS: All three subjects showed excellent audiological outcomes with rapid improvement of speech perception test result reaching plateau at 3 months after CI, although distribution of the disease predicted poor outcome based on theoretical analysis. CONCLUSIONS: This is the first report to present outcome of CI among subjects with a confirmed NLRP3 genetic etiology and resultant systemic inflammation, and suggests that CI is a viable treatment option in this disease entity.

Positional nystagmus in middle ear cholesteatoma with labyrinthine fistula.

Chronic otitis media with cholesteatoma can cause erosion of the dense labyrinthine bone overlying the inner ear organs, and this labyrinthine fistula allows pressure or mass-induced motion of the underlying perilymphatic and endolymphatic compartment, evoking vestibular symptoms. While the mechanism of a positive fistula test, which is conducted by increasing or decreasing the external auditory canal pressure, has been well established, the mechanism underlying positional nystagmus in labyrinthine fistula has not been discussed yet. In the present study, we propose a new hypothesis accounting for positional nystagmus in labyrinthine fistula involving the lateral semicircular canal (LSCC), i.e., the change in intracranial cerebrospinal fluid pressure by position change is transmitted to the perilymphatic space, causing ampullopetal (excitatory) or ampullofugal (inhibitory) deflection of the LSCC cupula.

Nystagmus in patients with lateral semicircular canal dysplasia.

BACKGROUND: Dizziness is not a common symptom in the lateral semicircular canal (LSCC) dysplasia, and nystagmus findings has been rarely described in LSCC dysplasia. OBJECTIVE: To investigate the characteristics of spontaneous and positional nystagmus in patients with LSCC dysplasia. METHODS: Patterns of spontaneous and positional nystagmus of twelve patients with LSCC dysplasia, who visited our clinic with a chief complaint of dizziness, were investigated. RESULTS: LSCC dysplasia was observed unilaterally in 4, and bilaterally in 8 patients. Non-rotatory dizziness with various onset times was the most common description of dizziness, and unilateral caloric weakness was observed in 82% of patients. Direction-fixed nystagmus, in which the direction of spontaneous nystagmus was same with that of positional nystagmus, was observed in 9 patients, and direction-changing positional nystagmus, in which the direction of nystagmus was changed from that of spontaneous nystagmus by positioning maneuvers, was observed in 3 patients, of whom down-beating or direction-changing spontaneous nystagmus was observed in one patient each. CONCLUSION: While direction-fixed horizontal nystagmus is the most commonly observed type of nystagmus in LSCC dysplasia, atypical spontaneous nystagmus, such as down-beating nystagmus or direction-changing spontaneous nystagmus, may be observed in patients with bilateral LSCC dysplasia.

Characteristic Analysis of Homo- and Heterodimeric Complexes of Human Mitochondrial Pyruvate Carrier Related to Metabolic Diseases.

Human mitochondrial pyruvate carriers (hMPCs), which are required for the uptake of pyruvate into mitochondria, are associated with several metabolic diseases, including type 2 diabetes and various cancers. Yeast MPC was recently demonstrated to form a functional unit of heterodimers. However, human MPC-1 (hMPC-1) and MPC-2 (hMPC-2) have not yet been individually isolated for their detailed characterization, in particular in terms of their structural and functional properties, namely, whether they exist as homo- or heterodimers. In this study, hMPC-1 and hMPC-2 were successfully isolated in micelles and they formed stable homodimers. However, the heterodimer state was found to be dominant when both hMPC-1 and hMPC-2 were present. In addition, as heterodimers, the molecules exhibited a higher binding capacity to both substrates and inhibitors, together with a larger structural stability than when they existed as homodimers. Taken together, our results demonstrated that the hetero-dimerization of hMPCs is the main functional unit of the pyruvate metabolism, providing a structural insight into the transport mechanisms of hMPCs.

Recombinant expression and purification of AF1q and its interaction with T-cell Factor 7.

The protein ALL1 fused from chromosome 1q (AF1q) is overexpressed in a variety of cancers and acts to activate several signaling pathways that lead to oncogenesis. For example, AF1q has been shown to interact with T-cell Factor 7 (TCF7; also known as TCF1) from the Wnt/ß-catenin pathway resulting in the transcriptional activation of the CD44 and the enhancement of breast cancer metastasis. Despite the importance of AF1q in facilitating oncogenesis and metastasis, the structural and biophysical properties of AF1q remain largely unexplored due to the absence of a viable method for producing recombinant protein. Here, we report the overexpression of AF1q in E. coli as a fusion to a N-terminal His6-tag, which forms inclusion bodies (IBs) during expression. The AF1q protein was purified from IBs under denaturing conditions by immobilized metal affinity chromatography followed by a successful one-step dialysis refolding. Refolded AF1q was further purified to homogeneity by gel filtration chromatography resulting in an overall yield of 35 mg/L culture. Our nuclear magnetic resonance (NMR) and analytical ultracentrifugation (AUC) measurements reveal AF1q interacts with TCF7, specifically with TCF7's high-mobility group (HMG) domain (residues 154-237), which is, to our knowledge, the first biophysical characterization of the AF1q and TCF7 interaction.

Natural Course of Unilateral Vocal Fold Paralysis and Optimal Timing of Permanent Treatment.

Importance: Permanent surgical treatment for unilateral vocal fold paralysis (UVFP) should be performed when further neural recovery is improbable. Conservative delay of the surgical procedure may cause unnecessary deterioration of the patient's quality of life. Knowledge of the natural course of UVFP is important for better management and counseling. Objective: To evaluate the natural course of UVFP, focusing on the recovery time according to the injury level to assess the optimal timing for permanent surgical intervention. Design, Setting, and Participants: This retrospective case series enrolled 1264 patients with UVFP who visited the voice clinic of Seoul National University Hospital, Seoul, Korea, from November 1, 2005, through December 31, 2016. Medical records and stroboscopic video images were reviewed to obtain data on demographic characteristics, vocal fold movement, onset and recovery time, follow-up duration, and cause. Cases of UVFP were classified into 5 groups based on the location of injury: distal to the thyroid level, thyroid level, esophagus and mediastinum level, heart and lung level, and proximal to the thorax level. Data analysis was performed from January 23, 2018, to May 21, 2018. Main Outcomes and Measures: Recovery of vocal fold movement defined as more than vocal fold twitching confirmed by stroboscopy video images, estimated injury level, and start time of recovery. The recovery time was analyzed according to age, sex, paralytic side, and 5 injury levels. Results: Of 1264 eligible patients with UVFP (655 [51.8%] male; median age, 56 years [range, 1-90 years]), 208 had evidence of recovery with the recovery time relatively accurate. The maximum recovery time for the group with distal to the thyroid-level injury was 120 days; the group with thyroid-level injury, 157 days; the group with esophagus and mediastinum-level injury, 244 days; the group with heart and lung-level injury, 328 days; and the group with proximal to the thorax-level injury, 333 days with the exception of 1 outlier value (482 days). Recovery time did not differ according to age, sex, or paralytic side. As distance between the vocal fold and injury level increased, the maximum recovery time increased, plateauing at 1 year. Among the patients who showed recovery of the vocal fold movement, most patients with injuries distal to or at the level of the thyroid recovered within 6 months, whereas those with injury more distant from the vocal fold recovered within approximately 1 year. Conclusions and Relevance: A linear association between injury level and maximum recovery time was observed. The findings suggest that the decision to proceed with permanent phonosurgical treatment should be based on the level of injury associated with UVFP.

Solution structure and functional investigation of human guanylate kinase reveals allosteric networking and a crucial role for the enzyme in cancer.

Human guanylate kinase (hGMPK) is the only known enzyme responsible for cellular GDP production, making it essential for cellular viability and proliferation. Moreover, hGMPK has been assigned a critical role in metabolic activation of antiviral and antineoplastic nucleoside-analog prodrugs. Given that hGMPK is indispensable for producing the nucleotide building blocks of DNA, RNA, and cGMP and that cancer cells possess elevated GTP levels, it is surprising that a detailed structural and functional characterization of hGMPK is lacking. Here, we present the first high-resolution structure of hGMPK in the apo form, determined with NMR spectroscopy. The structure revealed that hGMPK consists of three distinct regions designated as the LID, GMP-binding (GMP-BD), and CORE domains and is in an open configuration that is nucleotide binding-competent. We also demonstrate that nonsynonymous single-nucleotide variants (nsSNVs) of the hGMPK CORE domain distant from the nucleotide-binding site of this domain modulate enzymatic activity without significantly affecting hGMPK's structure. Finally, we show that knocking down the hGMPK gene in lung adenocarcinoma cell lines decreases cellular viability, proliferation, and clonogenic potential while not altering the proliferation of immortalized, noncancerous human peripheral airway cells. Taken together, our results provide an important step toward establishing hGMPK as a potential biomolecular target, from both an orthosteric (ligand-binding sites) and allosteric (location of CORE domain-located nsSNVs) standpoint.

pH-responsive delivery of Griffithsin from electrospun fibers.

Human immunodeficiency virus (HIV-1) affects over 36 million people globally. Current prevention strategies utilize antiretrovirals that have demonstrated protection, but result in antiviral resistance, adverse toxicity, and require frequent administration. A novel biologic, griffithsin (GRFT), has demonstrated outstanding safety and efficacy against laboratory and primary HIV isolates and against intravaginal murine herpes simplex virus 2 (HSV-2) challenge, making it a promising microbicide candidate. However, transient activity and instability remain concerns surrounding biologic delivery, particularly in the harsh environment of the female reproductive tract (FRT). Recently, electrospun fibers (EFs) have demonstrated promise for intravaginal delivery, with the potential to conserve active agent until release is needed. The goal of this study was to fabricate and characterize pH-responsive fibers comprised of poly(lactic-co-glycolic acid) (PLGA) or methoxypolyethylene glycol-b-PLGA (mPEG-PLGA) with varying ratios of poly(n-butyl acrylate-co-acrylic acid) (PBA-co-PAA), to selectively release GRFT under pH-conditions that mimic semen introduction. Fibers comprised of mPEG-PLGA:PBA-co-PAA (90:10 w/w) demonstrated high GRFT loading that was maintained within simulated vaginal fluid (SVF), and pH-dependent release upon exposure to buffered and SVF:simulated semen solutions. Moreover, GRFT fibers demonstrated potent in vitro efficacy against HIV-1 and safety in vaginal epithelial cells, suggesting their future potential for efficacious biologic delivery to the FRT.

Prognostic value of FDG PET/CT during radiotherapy in head and neck cancer patients.

PURPOSE: To evaluate the prognostic value of 18F-fluorodeoxyglucose positron-emission tomography (FDG PET) with computed tomography (CT) before and during radiotherapy (RT) in patients with head and neck cancer. METHODS: Twenty patients with primary head and neck squamous cell carcinoma were enrolled in this study, of whom 6 had oropharyngeal cancer, 10 had hypopharyngeal cancer, and 4 had laryngeal cancer. Fifteen patients received concurrent cisplatin and 2 received concurrent cetuximab chemotherapy. FDG PET/CT was performed before RT and in the 4th week of RT. The parameters of maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis (TLG) of the primary tumor were measured, and the prognostic significance of each was analyzed with the Cox proportional hazards model. RESULTS: Higher TLG (>19.0) on FDG PET/CT during RT was a poor prognostic factor for overall survival (OS) (p = 0.001) and progression-free survival (PFS) (p = 0.007). In the multivariate analysis, TLG during RT as a continuous variable was significantly associated with OS and PFS rate (p = 0.023 and p = 0.016, respectively). Tumor response worse than partial remission at 1 month after RT was another independent prognostic factor for PFS (p = 0.024). Conclusions: Higher TLG of the primary tumor on FDG PET/CT during RT was a poor prognostic factor for OS and PFS in patients with head and neck cancer.

1H, 13C and 15N resonance assignment of human guanylate kinase.

Human guanylate kinase (hGMPK) is a critical enzyme that, in addition to phosphorylating its physiological substrate (d)GMP, catalyzes the second phosphorylation step in the conversion of anti-viral and anti-cancer nucleoside analogs to their corresponding active nucleoside analog triphosphates. Until now, a high-resolution structure of hGMPK is unavailable and thus, we studied free hGMPK by NMR and assigned the chemical shift resonances of backbone and side chain 1H, 13C, and 15N nuclei as a first step towards the enzyme's structural and mechanistic analysis with atomic resolution.

Simultaneous determination of fast and slow dynamics in molecules using extreme CPMG relaxation dispersion experiments.

Molecular dynamics play a significant role in how molecules perform their function. A critical method that provides information on dynamics, at the atomic level, is NMR-based relaxation dispersion (RD) experiments. RD experiments have been utilized for understanding multiple biological processes occurring at micro-to-millisecond time, such as enzyme catalysis, molecular recognition, ligand binding and protein folding. Here, we applied the recently developed high-power RD concept to the Carr-Purcell-Meiboom-Gill sequence (extreme CPMG; E-CPMG) for the simultaneous detection of fast and slow dynamics. Using a fast folding protein, gpW, we have shown that previously inaccessible kinetics can be accessed with the improved precision and efficiency of the measurement by using this experiment.