The combined treatment with orbital and pretarsal botulinum toxin injections in the management of poorly responsive blepharospasm.

Blepharospasm (BS) is a focal dystonia involving involuntary contractions of muscles around the eyes. Botulinum toxin (BoNT) is the most effective treatment for BS and the technique of injection changes depending on the clinical picture. Usually typical BS benefits from the injection in the orbital part of the orbicularis oculi (OOc) muscle (orbital injection), while BoNT injection in the pretarsal part of OOc muscle is helpful especially for the atypical BS (opening eyelid apraxia). The aim of this study was to compare the efficacy of two injection techniques, the orbital versus the combined (injection in both orbital and pretarsal part of OOc) in BS patients with unsatisfactory response to BoNT. Nineteen patients with typical BS not having a satisfactory response from BoNT treatment with the orbital injection (primary and secondary resistant patients) were studied. After 3 months from the last orbital injection patients received the combined injection; they were assessed with the JRS and BSDI scales after 4 weeks from the last orbital and the first combined injection. Statistical analysis showed a significant reduction (p < 0.05) of the mean score of JRS and BSDI scales comparing the combined with orbital injection. This study shows that the treatment of typical BS can have better results when BoNT is injected with the combined technique in primary and secondary resistant patients.

A reply to "Relevant factors in the eutrophication of the Uruguay River and the Río Negro".

A recent paper by Beretta-Blanco and Carrasco-Letelier (2021) claims that agricultural eutrophication is not one of the main causes for cyanobacterial blooms in rivers and artificial reservoirs. By combining rivers of markedly different hydrological characteristics e.g., presence/absence and number of dams, river discharge and geological setting, the study speculates about the role of nutrients for modulating phytoplankton chlorophyll-a. Here, we identified serious flaws, from erratic and inaccurate data manipulation. The study did not define how erroneous original dataset values were treated, how the variables below the detection/quantification limit were numerically introduced, lack of mandatory variables for river studies such as flow and rainfall, arbitrary removal of pH > 7.5 values (which were not outliers), and finally how extreme values of other environmental variables were included. In addition, we identified conceptual and procedural mistakes such as biased construction/evaluation of model prediction capability. The study trained the model using pooled data from a short restricted lotic section of the (large) Uruguay River and from both lotic and reservoir domains of the Negro River, but then tested predictability within the (small) Cuareim River. Besides these methodological considerations, the article shows misinterpretations of the statistical correlation of cause and effect neglecting basic limnological knowledge of the ecology of harmful algal blooms (HABs) and international research on land use effects on freshwater quality. The argument that pH is a predictor variable for HABs neglects overwhelming basic paradigms of carbon fluxes and change in pH because of primary productivity. As a result, the article introduces the notion that HABs formation are not related to agricultural land use and water residence time and generate a great risk for the management of surface waterbodies. This reply also emphasizes the need for good practices of open data management, especially for public databases in view of external reproducibility.

Centennial glacier retreat increases sedimentation and eutrophication in Subantarctic periglacial lakes: A study case of Lake Uruguay.

High resolution XRF scanning documented inter-annual paleolimnological changes of a Subantarctic periglacial lake, during a process of centennial glacier retreat in King George Island, Antarctica. Two major paleoenvironmental stages were inferred from the combined analysis of elemental, molecular and isotopic biomarkers, with a boundary or transition set at about 3200 yr BP. The first stage was characterized by a relatively low allochthonous organic content, reduced productivity and nitrogen levels. Such paleoenvironmental conditions are interpreted as a terrestrial system under periglacial influence, where material influx was related to erosion process from the melt water discharge, because of the proximity to the Collins Glacier ice cap. After the major Holocene glacier advance dated at about 3500 yr BP, the ice cap retreat led to the formation of Lake Uruguay, which involved in filling processes leading to moraine deposits, proglacial meltwater channels, and lakes next to the land glacier. During the second stage, with the onset of the Current Warm Period, prior to 1900 CE the stabilization of the Zr/Rb ratio within the laminated sediments documented the origin of the lacustrine sedimentation system, with subsequent increases in the sedimentation rate and biomass content (total nitrogen and organic carbon). Time series analyses revealed that the lake displayed variability cycles related to El Niño Southern Oscillation (ENSO), as reflected by high resolution sedimentological proxies for grain size, weathering, allochthonous inputs from the watershed, increase of biomass and productivity, and changes in redox conditions, all of which displayed similar oscillation cycles from 2 to 6 yr. During this periglacial recession and associated eutrophication process, we detected a striking loss in both bacterial specific richness and diversity as inferred from preliminary selected ancient DNA analyses. Thus, the Antarctic warming scenario leading to glacier depletion appears to exert deterioration consequences on the Subantarctic microbial web.

Prosthetic replacement and tangential resection of the superior vena cava in chest tumors.

AIM: Infiltration of the superior vena cava (SVC) due to advanced non small cell lung cancer (NSCLC) or thymoma can be treated by prosthetic replacement or tangential resection. These two technical procedures and their results are described. METHODS: From 1988 to 2002, we performed 37 SVC resections: 21 replacements with polytetrafluoroethylene (PTFE) prostheses and 16 tangential exereses. Sixteen patients affected by locally advanced NSCLC (12 T4; 4 extracapsular N2) and 5 subjects with thymoma (Stage III Masaoka) underwent prosthetic replacement of the SVC. After neoadjuvant polychemotherapy, tangential resection was performed on 12 patients with extracapsular N2 NSCLC, and in 1 patient with T4 and in 3 patients with T3a disease. We performed prosthetic replacement in 18 cases using a straight prosthesis (?18-20 mm). A bridge (10-14 cm) between the innominate vein and the right atrium was created in 3 patients. The main indication for a prosthetic replacement was infiltration of more than 30% of the circumference of the SVC. There were 4 thromboembolic complications (19%), with one intraoperative death (4.8%). Tangential resection of the SVC for infiltration <20% was performed both manually and with staplers (double clamping) without any major complications. RESULTS: Mean survival was 23 months in those patients who had undergone PTFE replacement for T4 lung cancer and for thymoma. Mean survival was 15 months in those who had undergone tangential resections for NSCLC with extracapsular N2. We performed restaging of the tumor using chest angio-CT scan in 11 patients, one year after the operation. We found 80% patency in 7 SVC prostheses and 50% patency in 4 others: the two bridges between the left innominate vein and the right atrium appeared to be partially closed but were compensated by important collateral circles. CONCLUSION: SVC replacement, associated with pulmonary resection or removal of mediastinal masses, can be performed in selected cases. It should not be considered as palliative treatment because of the important perioperative risks. SVC tangential resection involves fewer surgical problems. However, since this procedure is used mostly for N2 NSCLC subjects, patients have a low mean survival in spite of adjuvant therapy.

Regional and local environmental conditions do not shape the response to warming of a marine habitat-forming species.

The differential response of marine populations to climate change remains poorly understood. Here, we combine common garden thermotolerance experiments in aquaria and population genetics to disentangle the factors driving the population response to thermal stress in a temperate habitat-forming species: the octocoral Paramuricea clavata. Using eight populations separated from tens of meters to hundreds of kilometers, which were differentially impacted by recent mortality events, we identify 25 °C as a critical thermal threshold. After one week of exposure at this temperature, seven of the eight populations were affected by tissue necrosis and after 30 days of exposure at this temperature, the mean % of affected colonies increased gradually from 3 to 97%. We then demonstrate the weak relation between the observed differential phenotypic responses and the local temperature regimes experienced by each population. A significant correlation was observed between these responses and the extent of genetic drift impacting each population. Local adaptation may thus be hindered by genetic drift, which seems to be the main driver of the differential response. Accordingly, conservation measures should promote connectivity and control density erosion in order to limit the impact of genetic drift on marine populations facing climate change.

Conversion of a CHO cell culture process from perfusion to fed-batch technology without altering product quality.

During the development of a new drug product, it is a common strategy to develop a first-generation process with the aim to rapidly produce material for pre-clinical and early stage clinical trials. At a later stage of the development, a second-generation process is then introduced with the aim to supply late-stage clinical trials as well as market needs. This work was aimed at comparing the performance of two different CHO cell culture processes (perfusion and fed-batch) used for the production of a therapeutically active recombinant glycoprotein at industrial pilot-scale. The first-generation process was based on the Fibra-Cel packed-bed perfusion technology. It appeared during the development of the candidate drug that high therapeutic doses were required (>100mg per dose), and that future market demand would exceed 100 kg per year. This exceeded by far the production capacity of the first-generation process, and triggered a change of technology from a packed-bed perfusion process with limited scale-up capabilities to a fed-batch process with scale-up potential to typical bioreactor sizes of 15m(3) or more. The productivity per bioreactor unit volume (in product m(-3)year(-1)) of the fed-batch process was about 70% of the level reached with the first-generation perfusion process. However, since the packed-bed perfusion system was limited in scale (0.6m(3) maximum) compared to the volumes reached in suspension cultures (15m(3)), the fed-batch was selected as second-generation process. In fact, the overall process performance (in product year(-1)) was about 18-fold higher for the fed-batch compared to the perfusion mode. Data from perfusion and fed-batch harvests samples indicated that comparable product quality (relative abundance of monomers dimers and aggregates; N-glycan sialylation level; isoforms distribution) was obtained in both processes. To further confirm this observation, purification to homogeneity of the harvest material from both processes, followed by a complementary set of studies (e.g. full physico-chemical characterization, assessment of in vitro and in vivo bioactivity, comparative pharmacokinetics and pharmacodynamics studies in relevant species, etc.) would be required. Finally, this illustrates the need to fix the production process early during the development of a new drug product in order to minimize process conversion efforts and to shorten product development time lines.

Comparative analytical characterization of two commercial human follicle-stimulating hormones extracted from human urine.

OBJECTIVE: Pharmaceutical preparations of human menopausal gonadotrophin (hMG), urine-derived follicle-stimulating hormone (u-FSH) and highly purified u-FSH (u-FSH-HP) have been available since the early 1960s and the mid 1980s and 1990s, respectively. Another commercial preparation of u-FSH-HP, Folyrmon P, was launched in Japan in 1999. The aim of this study is to assess the purity of Folyrmon P and to compare it with Fertinorm-P, another commercial preparation of u-FSH-HP that has been available since 1993. METHODS: Folyrmon P and Fertinorm-P were assessed for total protein content, biological activity, immunological activity, specific activity, purity and levels of protein contamination. RESULTS: Folyrmon P, which is extracted from the urine of post-menopausal women, has a specific activity of between 4000 and 5000 IU/mg, while Fertinorm-P, which is also manufactured from the urine of post-menopausal women, has a specific activity of at least 10,000 IU/mg. It has been well documented that commercially available hMG and u-FSH preparations can contain a number of urine-derived protein contaminants. This also proves to be the case for Folyrmon P, in which contaminant proteins other than FSH were shown to be present. It was also demonstrated that both preparations, Folyrmon P and Fertinorm-P, contained high levels of oxidized FSH. CONCLUSIONS: The low specific activity and high level of contaminants in Folyrmon P indicate that this u-FSH is not highly purified. Overall, Fertinorm-P, with higher specific activity and lower levels of contaminant proteins, appears to be of higher quality compared with Folyrmon P.

How many alien hand syndromes? Follow-up of a case.

We report the follow-up of a patient affected by a persistent alien left nondominant hand. CT and MRI showed an ischemic lesion localized to the mesial frontal region and involving the supplementary motor area and anterior fibers of the corpus callosum. These findings support theories suggesting a critical role of both these lesions in determining "chronic" forms of alien hand of either upper limb.

Trochanteric sciatic neuropathy.

A patient with severe weakness, atrophy, and sensory loss of the right leg had a focal right sciatic neuropathy. The sciatic nerve was enlarged at the level of the lesser trochanter, excessively firm, and multistranded; its stimulation threshold was focally increased. Biopsied fascicles had reduplicated perineurial leaflets, many Renaut bodies, and an abnormal unimodal spectrum of small-diameter fibers. We postulate that the lesion was induced by the combination of an underlying prominent lesser trochanter and sitting on hard benches.

Simultaneous total aortic replacement from valve to bifurcation: experience with 21 cases.

From June 1985 to December 1991, 21 patients (12 men and 9 women; mean age, 60 years) underwent total simultaneous aortic replacement that extended from the valve to the bifurcation. The causes of the diseased aorta were: medial degeneration with total aortic dilatation or multiple aneurysms (n = 7) and either acute (n = 4) or chronic (n = 10) dissection. Clinical evaluation and investigation in all patients consisted of computed tomography and magnetic resonance imaging as well as angiography. Only patients with combined thoracic and abdominal emergencies were selected, and these comprised worsening of cardiac conditions resulting from aortic regurgitation, and rapid dilatation of the ascending aorta and arch with impending rupture in conjunction with ischemia of the abdominal viscera, kidney, or either leg. The surgical technique consisted of inducing deep hypothermia by means of femoral vein-femoral artery cardiopulmonary bypass. During the cooling time, the aortic root was replaced under cardioplegia. Once lowering of the body temperature attained electroencephalographic silence, circulation was stopped and the aorta was replaced from the arch to the bifurcation. Circulation and rewarming were resumed only after the operation was completed. In our most recent patient, the operating time was reduced by opening the thoracic and the abdominal incisions during cooling; the cardioplegic solution as not injected but, instead, the myocardium was cooled down along with the whole body. In these patients, the hypothermy at electroencephalographic silence ranged from 14 degrees to 19 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Excision of the aortic wall in the surgical treatment of acute type-A aortic dissection.

Between March 1986 and September 1988, 38 patients underwent extended aortic resection (aortic valve, ascending aorta, and arch) for acute type-A aortic dissection with aortic valve insufficiency; deep hypothermia and circulatory arrest were used. All patients were operated on within 17 hours of the onset of symptoms. In the first 24 patients, operation was performed by the "inclusion technique." In the last 14 patients, the "excision technique" was used: the ascending aorta and arch was excised, and the aorta was transected at the beginning of the descending thoracic tract. Excision and transection were considered essential to prevent back flow from the false lumen, which is the main source of bleeding, and to allow all anastomoses to be constructed beyond the limits of dissection. The only anastomosis to the dissected aorta was at the distal end of the graft. One of the 14 patients died (7.1%). One patient was reopened for bleeding: blood was issuing from the attachment of the carotid trunks, and the defect was repaired by interposing a bifurcated Dacron graft between the arch graft and the carotid arteries. Extended aortic excision meets the principle of either eliminating as far as possible the diseased aorta or controlling intraoperative and postoperative bleeding. An operation of great magnitude can be considered a life-saving procedure when compared with the high risk of acute type-A aortic dissection.

Absent innervation of skin and sweat glands in congenital insensitivity to pain with anhidrosis.

OBJECTIVES: A case of a 10-year-old girl with congenital insensitivity to pain with anhidrosis (CIPA) is reported. METHODS AND RESULTS: Parents referred several hyperpyretic episodes without sweating occurring since birth, and insensitivity to pain, noticed when the child was 2 years old. Her body had many bruises and scars, bone fractures and signs of self-mutilation. Neurological examination was normal except for insensitivity to pain. Her IQ was 52. Electrical and tactile sensory nerve conduction velocities were normal. The patient was unable to detect thermal stimuli. Histamine injection evoked a wheal but not a flare; pilocarpine by iontophoresis did not induce sweat. Microneurography showed neural activity from A-beta sensory fibers while nociceptive and skin sympathetic C fiber nerve activity was absent. No small myelinated fibers and very rare unmyelinated fibers were found in the sural nerve. Immunohistochemistry showed a lack of nerve fibers in the epidermis and only few hypotrophic and uninnervated sweat glands in the dermis. CONCLUSIONS: The lack of innervation of the skin (C and A-delta fibers) appears to be the morphological basis of insensitivity to pain and anhidrosis, and is consistent with the loss of unmyelinated and small myelinated fibers in the sural nerve biopsy.

Is early onset cerebellar ataxia with retained tendon reflexes identifiable by electrophysiologic and histologic profile? A comparison with Friedreich's ataxia.

An electrophysiologic and histologic study was performed on 18 patients affected by early onset cerebellar ataxia with retained tendon reflexes (EOCA). Sensory and motor conduction velocity (SCV, MCV) was measured along peripheral nerves in all patients, somatosensory (SSEP) and brainstem auditory evoked potentials (BAEP) were recorded in 13; cortical stimulation (CS) in 12, and sural nerve biopsy in 4 patients were also performed. The results as a whole allow a division of EOCA patients into 2 groups: with (7 patients) and without (11 patients) peripheral neuropathy. Among EOCA patients with neuropathy a differential diagnosis with Friedreich's disease patients was not possible according to BAEPs and CS, while SSEPs could differentiate 2 out 5 patients in whom they were performed.

Intervertebral disc lesions in diffuse idiopathic skeletal hyperostosis (DISH).

OBJECTIVE: In order to evaluate the relationships between DISH and vertebral osteochondrosis (degenerative disc disease), the radiographs of the spine of 69 DISH patients were compared to those of 68 controls. METHODS: Radiographs of 69 patients affected by DISH according to Resnick's criteria and of 68 control subjects affected by diseases other than DISH, were evaluated in order to determine the prevalence of vertebral osteochondrosis, diagnosed by the occurrence of moderate to severe reduction in the intervertebral disc height and of the extensive radiographic changes typical of degenerative disc disease, including vacuum phenomena and vertebral body marginal sclerosis. The rate ratios with 95% confidence intervals were computed, with stratification by age groups. RESULTS: Thirty-eight DISH patients (55.1%) and 34 controls (50%) showed vertebral osteochondrosis. Stratification by age revealed an increased prevalence of vertebral osteochondrosis in younger DISH patients with respect to controls (p < 0.05). CONCLUSION: Our results show that vertebral osteochondrosis may be associated with DISH and underline the differences between classification and diagnostic criteria. Moreover, it could be hypothesized that DISH plays a predisposing role in the development of vertebral osteochondrosis during the early stages of the disease, causing an early modification in the physiological curves of the spine.

Autosomal recessive motor and sensory neuropathy with excessive myelin outfolding in two siblings.

Two siblings, a 35-year-old male and a 37-year-old female, offspring of first cousins, presented with a hereditary motor and sensory neuropathy with type I clinical features which began to manifest at about age 10 years. Nerve biopsy in the proband showed it to be a type characterized by excessive myelin outfolding. Morphometric study revealed hypomyelination with focal thickenings due to outfoldings. Clinical, electrophysiological and morphological findings are virtually identical to those described by Ohnishi et al. The peculiarity of the neuropathological picture suggests a particular form of hereditary motor and sensory neuropathy.

Evidence that Charcot-Marie-tooth disease with tremor coincides with the Roussy-Levy syndrome.

We report data on 3 members of a family affected by a dominantly inherited disorder closely resembling Roussy-Levy syndrome (RLS). Electrophysiological findings showed a marked decrease of motor and sensory conduction velocities and EMG signs of mild neurogenic damage. Light and electron microscopy of sural nerve biopsy showed a hypertrophic neuropathy with diffuse onion-bulb formations and marked decrease of large size fibers. Teased fiber preparations evidenced reduced internodal lengths and segmental demyelination. Other data from the literature on RLS are reviewed and discussed. The hypothesis that RLS is not a disease entity but a hypertrophic-type of Charcot-Marie-Tooth disease with essential tremor (HMSN type 1) is strongly supported.

POEMS syndrome: follow-up study of a case.

We report here the case of a 20-year-old man with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M proteins, skin changes). This rare syndrome followed a 3-year history of a syndrome that mimics a chronic inflammatory demyelinating polyneuropathy (CIDP). Treatment with cyclophosphamide induced regression of the syndrome and improved peripheral nerve conduction.

A case of Dejerine-Sottas disease with prominent ataxia and brain stem involvement. A clinical, electrophysiological, otoneurologic, and ultrastructural study.

A case is presented of Dejerine-Sottas disease in a 12-year-old boy in which clinical signs made diagnosis of Friedreich's ataxia seem plausible. Based on marked slowing of motor conduction velocity, the sural nerve biopsy findings of a hypertrophic neuropathy with hypo- and demyelination of the nerve fibres, as well as the clinical history, the diagnosis of Dejerine-Sottas disease was made. ABR examination suggested involvement of brain stem at the roots and/or nuclei of the eighth cranial nerve, without involvement of higher structures.

Experimental model of nervous anastomosis between intercostal and lumbar nerves in the rabbit.

The authors propose a new experimental model of nervous anastomosis between intercostal and lumbar nerves in rabbit with the purpose of providing a technique to by-pass a spinal lesion. Before carrying out the surgical experiments, an histological study has been performed on the donor and receiver nerves which demonstrated the great difference in number of nervous fiber between these two nerves. The purpose of the method is thus to reinnerve a lumbar nerve by means of two intercostal nerves. Histological controls are performed on the 120th day.

A family with tomaculous neuropathy mimicking Charcot-Marie-Tooth disease.

The appearance of Guillain-Barré syndrome in a 9-year-old girl led to the detection of a hereditary neuropathy in her family. This neuropathy showed clinical and electrophysiological characteristics of Charcot-Marie-Tooth disease. Only nerve biopsy performed in a sister of the proband allowed diagnosis of tomaculous neuropathy which presented unusual clinical, electrophysiological and bioptic aspects.