Fractionated radiotherapy for surgically resected intracranial meningiomas: A multicentre retrospective cohort study.

BACKGROUND: Aside from surgical resection, the only standard of care treatment modality for meningiomas is radiotherapy (RT). Despite this, few studies have focused on identifying clinical covariates associated with failure of fractionated RT following surgical resection (fRT), and the timing of fRT following surgery still remains controversial (adjuvant versus salvage fRT). We assessed the outcomes of the largest, multi-institutional cohort of surgically resected meningiomas treated with subsequent adjuvant and salvage fRT to identify factors associated with local freedom from recurrence (LFFR) over 3-10 years post-fRT and to determine the optimal timing of fRT. METHODS: Patients with intracranial meningiomas who underwent surgery and fRT between 1997 and 2018 were included. Primary endpoints were radiographic recurrence/progression and time to progression from the completion of fRT. RESULTS: 404 meningiomas were included for analysis. Of these, 167 (41.3%) recurred post-fRT. Clinical covariates independently associated with worse PFS post-fRT included receipt of previous RT to the meningioma, having a WHO grade 3 meningioma or recurrent meningioma, the meningioma having a higher MIB1-index or brain invasion on pathology, and older patient age at diagnosis. Subgroup analysis identified higher MIB1-index as a histological factor associated with poorer LFFR in WHO grade 2 meningiomas. 179 patients underwent adjuvant RT shortly after surgery whereas 225 patients had delayed, salvage fRT after recurrence/progression. Following propensity score matching, patients that underwent adjuvant fRT had improved LFFR post-fRT compared to those that received salvage fRT. CONCLUSION: There is a paucity of clinical factors that can predict a meningioma's response to fRT following surgery. Adjuvant fRT may be associated with improved PFS post-fRT compared to salvage fRT. Molecular biomarkers of RT-responsiveness are needed to better inform fRT treatment decisions.

Outcomes and predictors of response to fractionated radiotherapy as primary treatment for intracranial meningiomas.

Background: Surgery is the primary treatment for most meningiomas. However, primary fractionated radiotherapy (fRT) remains an option for patients with larger meningiomas in challenging anatomic locations or patients at prohibitively high surgical risk. Outcome prediction for these patients is uncertain and cannot be guided by histopathology without available tumor tissue from surgery. Therefore, we aimed to assess the clinical factors that contribute to treatment failure in a large cohort of meningiomas consecutively treated with fRT as primary therapy, with the goal of identifying predictors of response. Methods: Patients treated with primary fRT for intracranial meningiomas from 1998 to 2017 were reviewed. Those who received primary surgical resection, radiosurgery, previous fRT, or had <6 months of clinical follow-up were excluded. We applied logistic regression and Cox regression modeling to ascertain key predictors of treatment failure, progression-free survival (PFS), and adverse events (AE) following fRT. Results: Our cohort included 137 meningiomas, 21 of which progressed after fRT (median PFS 3.45 years). Progressive meningiomas had a larger median gross tumor volume (GTV) compared to those that remained stable (19.1 cm3 vs 9.6 cm3, p = 2.86 × 10-2). GTV > 11.27 cm3 was independently predictive of progression and larger GTV was associated with higher risk of significant (grades 3/4) AE following fRT. Cavernous sinus and optic nerve sheath meningiomas had overall excellent outcomes post-fRT. Conclusions: We present a large cohort of meningiomas treated with primary fRT and find GTV and anatomic location to be key predictors of outcome, adding to the complex treatment considerations for this heterogeneous disease.

The effect of supraphysiological dose of nandrolone decanoate administration on the inflammatory, neurotrophin and behavioral response in adult and old male mice.

This study examined the effect of 6 weeks of supraphysiological nandrolone decanoate (ND) administration in adult mice (7 months) on cognitive function and neuroinflammation during aging. Male C57BL/6 mice were randomized into ND (10 mg·kg-1·wk-1) or control (CTL) groups. Half of the mice were tested at a young (Y) age (ND-Y and CTL-Y), 1 week following final ND administration, while the remaining mice were tested at 16 months (O) (ND-O and CTL-O). Learning and memory were better in young mice compared to older mice, regardless of treatment. ND-O displayed decreased anxiety as compared to all other groups. TNFα and IL1ß expression were higher in older mice, regardless of treatment. ND administration in young mice appeared to attenuate the neuroinflammatory response in aging mice as evidenced by decreased COX2, IL-4 and increased IL-10 expression in ND-O compared to CTL-O. BDNF AR and ER expression increased in ND-O compared to CTL-O. Results of the study indicated that supraphysiological ND administration had no negative effect on learning and memory but may attenuate anxiety in older mice. In addition, ND administration in young adult mice may attenuate the inflammatory response during aging, which may be related to elevations in both AR and ER expression.

Fistulectomy and incontinence: do we really need to worry?

Background: Anal fistula is often considered to be a dilemma because of the need to maintain a fine balance between postoperative incontinence and recurrence. We tried to find whether apprehension of causing incontinence should stop us from performing fistulectomy. The aim of this study was to determine whether fistulectomy was associated with increased rate of fecal incontinence and recurrence, compared to other procedures used for the treatment of anal fistula. Methods: It was a prospective, single center, observational study. All patients with anal fistula operated at a tertiary care teaching institute over a period of two years were included in the study. Recurrence rates and fecal incontinence were compared between patients subjected to fistulectomy and other procedures for treatment of fistula in ano. Results: A total of 124 patients with anal fistula were included. 92.8% patients were ≤ 60 years of age with high male preponderance (89.5%). Perineal discharge was the commonest complaint (95.96%). Intersphincteric (47.58%) followed by transphincteric fistulas (45.16%) accounted for the majority of fistulas. Fistulectomy was the most common procedure, performed in 90 (72.58%) patients. Incontinence occurred in 8/90 (8.88%) from the fistulectomy group and 2/34 (5.9%) patients in other surgery group, p=0.726. Recurrence occurred in 8/90 (8.88%) from the fistulectomy group and 8/34 (23.5%) patients from other surgery group, p=0.038. Overall rates of incontinence and recurrence were 8.1% and 12.9% respectively. Conclusion: Fistulectomy, as compared to other procedures, results in less chances of recurrence without compromising continence.

Applications of Machine Learning to Imaging of Spinal Disorders: Current Status and Future Directions.

STUDY DESIGN: Narrative review. OBJECTIVES: We aim to describe current progress in the application of artificial intelligence and machine learning technology to provide automated analysis of imaging in patients with spinal disorders. METHODS: A literature search utilizing the PubMed database was performed. Relevant studies from all the evidence levels have been included. RESULTS: Within spine surgery, artificial intelligence and machine learning technologies have achieved near-human performance in narrow image classification tasks on specific datasets in spinal degenerative disease, spinal deformity, spine trauma, and spine oncology. CONCLUSION: Although substantial challenges remain to be overcome it is clear that artificial intelligence and machine learning technology will influence the practice of spine surgery in the future.

A review of 'medical' knowledge of epilepsy amongst isiZulu-speaking patients at a regional hospital in KwaZulu-Natal.

BACKGROUND: Epilepsy is a common disorder in South Africa and the literature indicates that many patients do not access treatment. The reasons are complex and include a poor knowledge about causes, symptoms, diagnosis and treatment (medical knowledge). This study aimed to assess the medical knowledge of isiZulu-speaking people with epilepsy (PWE) who attend a combination regional and district hospital in the eThekwini district in KwaZulu-Natal Province. METHOD: This was a prospective, cross-sectional, descriptive study. Data were collected using a validated data collection tool for assessing the medical knowledge of PWE and analysed descriptively. RESULTS: The questionnaires were completed by 199 PWE, with the general level of schooling being low and half being unemployed. Knowledge around causes, symptoms, diagnosis and treatments was good, but there were significant gaps in knowledge that may affect morbidity and mortality. DISCUSSION: The findings will serve as a useful guide to develop both preventive and educational interventions to enhance knowledge around the causes and treatment of epilepsy in this population. It is important that such interventions also consider family and healthcare providers. CONCLUSION: There were considerable gaps in the medical knowledge of isiZulu-speaking PWE's, indicating the need for an educational intervention to improve their understanding of epilepsy. Further research is needed-using a range of tools to ensure that the data is reliable and valid-if the results are to be generalisable to the rest of the province and South Africa.

Allele frequencies of nine STR loci of Jewish and Arab populations in Israel.

DNA typing of nine short tandem repeat (STR) loci was carried out on unrelated Israeli Jewish and Arab individuals. All loci were highly polymorphic and the distribution of the obtained genotypes did not deviate from Hardy-Weinberg equilibrium. A comparison between Jewish and Arab population data revealed statistically significant differences in allele frequency distributions for some of the loci. The results presented in this study enable the use of these nine STR loci for forensic, identification and paternity cases in the Jewish and the Arab populations of Israel.

Fingerprints and DNA: STR typing of DNA extracted from adhesive tape after processing for fingerprints.

An exhibit that is often received for examination in cases of robbery or terrorist activity is adhesive tape. This type of exhibit can often, but not always, be successfully processed for fingerprints. The question arises whether or not it is possible to extract and type DNA after the tape has been sequentially processed for fingerprints. In this work, various donors left fingerprints on the adhesive side of tapes. The tapes were then sequentially processed for fingerprints using an alternate light source, cyanoacrylate fuming, and staining with BY-40 and then crystal violet. DNA was subsequently successfully extracted, amplified and typed for six STR loci.

Light-harvesting complex II pigments and proteins in association with Cbr, a homolog of higher-plant early light-inducible proteins in the unicellular green alga Dunaliella.

Like higher plants, unicellular green algae of the genus Dunaliella respond to light stress by enhanced de-epoxidation of violaxanthin and accumulation of Cbr, a protein homologous to early light-inducible proteins (Elips) in plants. Earlier studies indicated that Cbr was associated with the light-harvesting complex of photosystem II (LHCII) and suggested it acted as a zeaxanthin-binding protein and fulfilled a photo-protective function (Levy et al. 1993, J. Biol. Chem. 268: 20892-20896). To characterize the protein-pigment subcomplexes containing Cbr in greater detail than attained so far, thylakoid membranes from Dunaliella salina grown in high light or normal light were solubilized with dodecyl maltoside and fractionated by isoelectric-focusing. Analysis of the resolved LHCII subcomplexes indicated preferred associations among the four LHCIIb polypeptides and between them and Cbr: subcomplexes including Cbr contained one or two of the more acidic of the four LHCIIb polypeptides as well as large amounts of lutein and zeaxanthin relative to chlorophyll a/b. After sucrose gradient centrifugation, Cbr free of LHCIIb polypeptides was detected together with released pigments; this Cbr possibly originated in subcomplexes dissociated in the course of the analysis. These results agree with the conclusion that Cbr is part of the network of LHCIIb protein-pigment complexes and suggest that the role played by Cbr involves the organization and/or stabilization of assemblies highly enriched in zeaxanthin and lutein. Such assemblies may function to protect PSII from photodamage due to overexcitation.

Threat mail and forensic science: DNA profiling from items of evidence after treatment with DFO.

Two cases of threatening letters with their accompanying envelopes were received to the Division of Forensic Identification unit of the Israel Police. The envelopes, including the stamps, and the letters were initially examined for latent fingerprints by the DFO reagent, known to cause degradation of DNA. Although no latent fingerprints could be visualized on any of the items, the biology laboratory using organic DNA extraction, was successful in defining genetic profiles from all the items employing six STR loci, even after treatment with DFO. In a controlled experiment, a known donor attached a stamp, by licking, to an envelope. This item was treated with DFO and then profiled using STR loci. The results showed that previous DFO treatment on the control stamp before DNA analysis had no negative effects on obtaining the DNA profile of the known donor using STR loci.

An evaluation of the relevance of routine DNA typing of fingernail clippings for forensic casework.

DNA extracted from fingernail clippings of victims in forensic cases is a possible source of DNA from the perpetrator in cases where victims struggled or defended themselves. The source of this DNA on a victim's fingernails could possibly originate from contact with the suspect's blood, saliva, semen or scratched skin. In this technical note we evaluate the relevance of routine DNA typing of fingernail clippings in the forensic biology laboratory when, in real casework, normally only small quantities of nail material is sent. This was carried out by extracting DNA from fingernail clippings from a number of volunteers, before and after aggressively scratching other volunteers. No blood was drawn from the scratching, but skin flakes were observed under the nails before cutting and subsequent DNA typing. The DNA extracted was then typed using the STR systems: HUMTHO1, HUMTPOX and HUMCSF1PO (CTT triplex) and the system of D1S80. These profiles were compared with profiles achieved by similar typing of buccal swabs as a reference from each volunteer. In this study, the profile detected from each volunteer's clippings was the same before and after scratching, and matched the profile of the corresponding volunteer as defined by typing each volunteer's reference buccal swab. Fingernail clippings that are sent to our lab in actual casework are usually so small that additional treatment by swabbing or removing debris from below the clipping is not possible. For this reason, in this simulation the entire clippings were used for DNA extraction, to maximize the possibility of finding an additional profile. In conclusion, the findings from this study show that although the profiles obtained when typing fingernail clippings are those of the donors themselves, we suggest that typing of fingernail clippings should be carried out in forensic cases only when relevant. We would suggest that fingernail clippings not be routinely sent to the biology laboratory as items of evidence to be tested.

Differential responses to different light spectral ranges of violaxanthin de-epoxidation and accumulation of Cbr, an algal homologue of plant early light inducible proteins, in two strains of Dunaliella.

Unicellular green algae of the genus Dunaliella, similar to higher plants, respond to light stress by enhanced de-epoxidation of violaxanthin and accumulation of Cbr, a protein homologous to early light inducible proteins (Elips) in plants. These proteins belong to the superfamily of chlorophyll a/b binding proteins. Two Dunaliella strains, D. bardawil and D. salina, were compared for these two responses under light in the UVA, blue, green and red spectral ranges. In D. bardawil, the two stress responses were similarly induced under UVA, blue or red light and to a lesser extent under green light. In D. salina, a similar spectral range dependence was exhibited for violaxanthin de-epoxidation. However, Cbr accumulated only under UVA or blue light but not under green or red light. A strong synergistic effect of a low dose of blue light superimposed on red light resulted in Cbr accumulation. These results reveal strain-specific differences in spectral range requirements of the two light-stress responses. In the two strains, violaxanthin de-epoxidation is triggered under photosynthetically-active spectral ranges but at least in D. salina, Cbr accumulation appears to require a specific light signal additionally to a signal(s) generated by light stress.

Immunoproliferative small intestinal disease in a 16-year-old boy presenting as severe malabsorption with excellent response to tetracycline treatment.

Immunoproliferative small intestinal disease (IPSID) is a rare lympho-proliferative disorder of the upper small intestine. It is considered a special form of MALT lymphoma with propensity to malignant transformation. This disorder is rare in pediatric literature. We report a case of IPSID in a 16-year-old boy with low-grade malignant transformation, presenting as severe malnutrition and a possible association with Helicobacter pylori. The patient responded well to an extended treatment with tetracycline and eradication of H. pylori.

Iron uptake by the halotolerant alga Dunaliella is mediated by a plasma membrane transferrin.

A 150-kDa transferrin-like protein (Ttf) is associated with the plasma membrane of the halotolerant unicellular alga Dunaliella salina (Fisher, M., Gokhman, I., Pick, U., and Zamir, A. (1997) J. Biol. Chem. 272, 1565-1570). The Ttf level rises with medium salinity or upon iron depletion. Evidence that Ttf is involved in iron uptake by Dunaliella is presented here. Algal iron uptake exhibits characteristics resembling those of animal transferrins: high specificity and affinity for Fe3+ ions, strict dependence on carbonate/bicarbonate ions, and very low activity in acidic pH. Reducing the level of Ttf by mild proteolysis of whole cells is accompanied by lowered uptake activity. Conversely, accumulation of high levels of Ttf is correlated with an enhancement of iron uptake. Kinetically, iron uptake consists of two steps: an energy-independent binding of iron to the cell surface and an energy-dependent internalization. Salinities as high as 3.5 M NaCl do not inhibit iron uptake or decrease the apparent affinity for Fe3+ ions, implying that Ttf activity is not affected by high salt. These results indicate that transferrins, hitherto identified only in animals, are present and function in iron transport also in plant systems.

A structurally novel transferrin-like protein accumulates in the plasma membrane of the unicellular green alga Dunaliella salina grown in high salinities.

The alga Dunaliella salina is outstanding is its ability to withstand extremely high salinities. To uncover mechanisms underlying salt tolerance, a search was carried out for salt-induced proteins. The level of a plasma membrane 150-kDa protein, p150, was found to increase with rising external salinity (Sadka, A., Himmelhoch, S., and Zamir, A. (1991) Plant Physiol. 95, 822-831). Based on its cDNA-deduced sequence, p150 belongs to the transferrin family of proteins so far identified only in animals. This, to our best knowledge, is the first demonstration of a transferrin-like protein in a photosynthetic organism. Unlike animal transferrins, p150 contains three, rather than two, internal repeats and a COOH-terminal extension including an acidic amino acid cluster. In intact cells p150 is degraded by Pronase, indicating that the protein is extracellularly exposed. The relationship of p150 to iron uptake is supported by the induction of the protein in iron-deficient media and by its radioactive labeling in cells grown with 59Fe. Accumulation of p150 is transcriptionally regulated. It is proposed that p150 acts in iron uptake other than by receptor-mediated endocytosis and that its induction permits the cells to overcome a possible limitation in iron availability under high salinities.

A salt-resistant plasma membrane carbonic anhydrase is induced by salt in Dunaliella salina.

The mechanisms allowing proliferation of the unicellular green alga Dunaliella salina in up to saturating NaCl concentrations are only partially understood at present. Previously, the level of a plasma membrane Mr 60,000 protein, p60, was found to increase with rising external salinities. Based on cDNA cloning and enzymatic assays, it is now shown that p60 is an internally duplicated carbonic anhydrase, with each repeat homologous to animal and Chlamydomonas reinhardtii carbonic anhydrases, but exceptional in the excess of acidic over basic residues. Increasing salinities, alkaline shift, or removal of bicarbonate induced in D. salina parallel increases in the levels of p60, its mRNA, and external carbonic anhydrase activity. Moreover, purified p60 exhibited carbonic anhydrase activity comparable to other carbonic anhydrases. A p60-enriched soluble preparation showed maximal carbonic anhydrase activity at approximately 1.0 M NaCl and retained considerable activity at higher salt concentrations. In contrast, a similar preparation from C. reinhardtii was approximately 90% inhibited in 0.6 M NaCl. These results identified p60 as a structurally novel carbonic anhydrase transcriptionally regulated by CO2 availability and exhibiting halophilic-like characteristics. This enzyme is potentially suited to optimize CO2 uptake by cells growing in hypersaline media.

Possible Role of Cbr, an Algal Early-Light-Induced Protein, in Nonphotochemical Quenching of Chlorophyll Fluorescence.

The unicellular green alga Dunaliella bardawil exhibits typical responses to excessive light when starved for sulfate under normal light (60 [mu]E m-2 s-1) but not under low light (14 [mu]E m-2 s-1). Algae were analyzed during several days of sulfate starvation for nonphotochemical quenching of chlorophyll fluorescence in the absence or presence of the uncouplers SF-6847 (SF) or carbonyl cyanide p- trifluoromethoxyphenyl hydrazone. Parallel analyses followed two light-stress responses: (a) violaxanthin conversion to zeaxanthin and (b) accumulation of Cbr, a protein analogous to plant early-light-induced proteins and implicated in zeaxanthin binding. In cells starved under normal light SF inhibited nonphotochemical quenching during the first 24 h, but not from 40 h onward. In cells starved under low light SF inhibited nonphotochemical quenching throughout the starvation period. Under normal light accumulation of zeaxanthin was nearly maximal by 24 h, but Cbr was fully induced only by 40h. Under low light zeaxanthin accumulated slowly but no Cbr was evident. These results suggest that during exposure to excessive light, the initial pH gradient-dependent, Cbr-independent mode of nonphotochemical quenching is modified to become less dependent on pH gradient and requires Cbr.

A Salt-Induced 60-Kilodalton Plasma Membrane Protein Plays a Potential Role in the Extreme Halotolerance of the Alga Dunaliella.

The halotolerant alga Dunaliella salina grows in saline conditions as varied as 0.5 and 5 M NaCl, maintaining throughout this range a low intracellular ion concentration. To discover factors potentially involved in ionic homeostasis, we grew cells in media with different salinities or osmolarities and compared their protein profiles. The comparisons indicated that the amount of a 60-kD protein, p60, greatly increased with an increase in salinity and was moderately enhanced when NaCl was substituted with iso-osmotic glycerol. Cells transferred from low to high NaCl or from high glycerol to iso-osmotic NaCl media transiently ceased to grow, and resumption of growth coincided approximately with an increase in p60. The protein, extracted from a plasma membrane fraction, was purified to homogeneity. Anti-p60 antibodies cross-reacted with a 60-kD protein in Dunaliella bardawil. Immunoelectron microscopy of D. salina cell sections indicated that p60 was exclusively located in the plasma membrane. Its induction by salt, the correlation between its accumulation and growth resumption in high concentrations of salt, and its plasma membrane localization suggest the possibility that p60 could play a role in ionic homeostasis in conditions of high salinity, although different types of function could also be considered.