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Polyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinson's disease and cancer, driving interest in therapeutically targeting this pathway. However, measuring cellular polyamine levels, which vary across cell types and states, remains challenging. We introduce a first-in-class genetically encoded polyamine reporter for real-time measurement of polyamine concentrations in single living cells. This reporter utilizes the polyamine-responsive ribosomal frameshift motif from the OAZ1 gene. We demonstrate broad applicability of this approach and reveal dynamic changes in polyamine levels in response to genetic and pharmacological perturbations. Using this reporter, we conducted a genome-wide CRISPR screen and uncovered an unexpected link between mitochondrial respiration and polyamine import, which are both risk factors for Parkinson's disease. By offering a new lens to examine polyamine biology, this reporter may advance our understanding of these ubiquitous metabolites and accelerate therapy development. .

Background: For rheumatic mitral stenosis (MS), a multidisciplinary evaluation is mandatory to determine the optimal treatment: medical, percutaneous balloon mitral valvuloplasty (PBMV) or valve surgery. Clinical and imaging evaluations are essential for procedural risk assessment and outcomes. PBMV interventions are increasingly available in Africa and are feasible options for selected candidates. Enhancing PBMV training/skills transfer across most of African countries is possible., Objectives: The aim of this study was to provide insight into the clinical practice of patients with rheumatic MS evaluated for PBMV in a Tanzanian teaching hospital and to define the role of imaging, and evaluate the heart team and training/skills transfer in PBMV interventions., Methods: From August 2019 to May 2022, 290 patients with rheumatic MS were recruited consecutively in the Tanzania Mitral Stenosis study. In total, 43 (14.8%) patients were initially evaluated for eligibility for PBMV by a heart team. We carried out the clinical assessment, laboratory investigations, transthoracic/oesophageal echocardiography (TTE/TEE) and electrocardiography., Results: The median age was 31 years (range 11-68), and two-thirds of the patients were female (four diagnosed during pregnancy). Two patients had symptomatic MS at six and eight years. Nine patients had atrial fibrillation with left atrial thrombus in three, and two were detected by TEE. Nine patients in normal sinus rhythm had spontaneous echo contrast. The mean Wilkins score was 8.6 (range 8-12). With re-evaluation by the local and visiting team, 17 patients were found to have unfavourable characteristics: Bi-commissural calcification (four), ≥ grade 2/4 mitral regurgitation (six), high scores and left atrial thrombus (three), left atrial thrombus (two), and severe pulmonary hypertension (two). Three patients died before the planned PBMV. Eleven patients were on a waiting list. We performed PBMV in 12 patients, with success in 10 of these, and good short-term outcomes [mean pre-PBMV (16.03 ± 5.52 mmHg) and post-PBMV gradients (3.08 ± 0.44 mmHg, p < 0.001)]. There were no complications., Conclusions: PBMV had good outcomes for selected candidates. TEE is mandatory in pre-PBMV screening and for procedural guidance. In our cohort, patients with Wilkins score of up to 11 underwent successful PBMV. We encourage PBMV skills expansion in low- and middle-income countries, concentrating on expertise centres.

The micronutrient selenium is incorporated via the selenocysteine biosynthesis pathway into the rare amino acid selenocysteine, which is required in selenoproteins such as glutathione peroxidases and thioredoxin reductases 1,2 . Here, we show that selenophosphate synthetase 2 (SEPHS2), an enzyme in the selenocysteine biosynthesis pathway, is essential for survival of cancer, but not normal, cells. SEPHS2 is required in cancer cells to detoxify selenide, an intermediate that is formed during selenocysteine biosynthesis. Breast and other cancer cells are selenophilic, owing to a secondary function of the cystine/glutamate antiporter SLC7A11 that promotes selenium uptake and selenocysteine biosynthesis, which, by allowing production of selenoproteins such as GPX4, protects cells against ferroptosis. However, this activity also becomes a liability for cancer cells because selenide is poisonous and must be processed by SEPHS2. Accordingly, we find that SEPHS2 protein levels are elevated in samples from people with breast cancer, and that loss of SEPHS2 impairs growth of orthotopic mammary-tumour xenografts in mice. Collectively, our results identify a vulnerability of cancer cells and define the role of selenium metabolism in cancer.

This experiment investigated the effect of dietary monensin on performance, nutrient utilisation, rumen volatile fatty acid and blood status in West African dwarf (WAD) goats fed with basal diets of forages. Four concentrate supplements were formulated to include 0 (MO), 15 (M15), 30 (M30) and 45 (M45) mg monensin/kg dry matter. Twenty-four WAD bucks (7.3 ± 1.20 kg initial body weight, aged 9-12 months) were randomly allotted to four experimental diets in a completely randomised design for 90 days, six animals per diet. Results indicated that animals fed M15, M30 and M45 diets had lower (P < 0.01) dry matter and water intake than those fed M0 diet. Crude protein and neutral detergent fibre intakes by the bucks followed similar trend. Animals on M15, M30 and M45 had better (P < 0.001) feed and protein efficiency ratio than those fed M0 diet. Rumen pH and total volatile fatty acid concentration were maintained (P > 0.05) while monensin decreased (P < 0.001) acetate/propionate ratio. Blood glucose increased (P < 0.001) from 59.1 mg/dl in animals on M0 diet to 67.8, 66.0 and 66.3 mg/dl in animals on M15, M30 and M45 diets. Overall, there were no variations among animals on M15, M30 and M45 diets. It is concluded that feeding monensin at 15 to 45 mg/kg DM of supplemental concentrate diets to West African dwarf bucks could be effective in improving feed and protein efficiency, manipulating the rumen for increased propionate production and increasing blood glucose levels.

Objective: Reduplicative paramnesia (RP) is thought to be related to other delusional misidentification syndromes (DMS) such as Capgras syndrome. DMS are thought to occur when brain lesions disrupt cortical functioning. This study tests this hypothesis and tries to understand whether focal lesions are as important in the etiology of RP as they are in other types of DMS., Method: The computed tomography (CT) scans of 10 consecutive psychiatric inpatients with RP and another principal psychiatric diagnosis were compared with those of control patients without RP matched for age, sex, and principal psychiatric diagnosis. The scans were assessed blindly by a neuroradiologist using a previously published rating scale for the presence of lesions in 11 discrete anatomic areas. The differences between the 2 groups were examined statistically using log-linear analysis., Results: Statistical analysis revealed that index patient cortical atrophy, cortical fissure enlargement, and deep brain atrophy distinguished the 2 groups significantly (P < 0.05)., Conclusions: Bilateral anterior cortical, brain stem, and cerebellar vermis atrophy and dysfunction may be important in the pathogenesis of RP in particular and of DMS in general.

Valproic acid, a primary anticonvulsant drug, has recently been studied for purported effectiveness in disparate disorders of mood and behaviour. The psychopharmacological treatment of patients with acquired brain injury frequently includes numerous trials of psychotherapeutic drugs such as antipsychotics, benzodiazepines, antidepressants, and lithium, in an effort towards affective and behavioural improvement. In this report we describe and graphically depict the striking efficacy of valproic acid in reducing and improving destructive and aggressive behaviours in five patients with acquired brain injury. In all cases valproic acid was effective after other pharmacological interventions were not. Also, the addition of valproic acid was followed by neurobehavioural improvement rather quickly, often within 1-2 weeks. Advantages of valproic acid, in addition to its possible unique efficacy, include a lower propensity towards sedation and cognitive impairment, and thus a more robust potential for rehabilitation participation. Behaviours associated with affective disorders ranging along the affective spectrum from depression to dysphoric mania may be particularly amenable to valproic acid. The drug may also be beneficial in some cases in which another psychotropic anticonvulsant, carbamazepine, was not.

Background: Untreated or poorly treated depression in patients who suffer from traumatic brain injury can result in greater functional disability and prolonged or ineffective hospital and rehabilitation stays. Literature available on the pharmacologic treatment of depression after traumatic brain injury is scarce. This study investigated in a controlled and prospective manner the use of desipramine, a tricyclic antidepressant, in a series of patients with severe traumatic brain injury., Method: Ten patients with severe traumatic brain injury and long-standing depression, as diagnosed by DSM-III-R criteria, were admitted to the study because of the intention to be treated with antidepressants. They were randomly assigned to blindly start on either desipramine treatment (N = 6) or placebo lead-in (N = 4). Patients starting with desipramine stayed on that drug; patients starting with placebo lead-in were blindly crossed over to desipramine after 1 month if there was no significant improvement demonstrated by DSM-III-R criteria. All rating clinicians, physicians, and patients were blind to actual treatment and any ratings data. DSM-III-R evaluations were done monthly. An affect/mood scale was done every 2 weeks., Results: Of all patients evaluable using the DSM-III-R, 6 (86%) of 7 demonstrated resolution of depression and depressed mood during desipramine treatment. (Three received desipramine throughout the study; 3 others started taking placebo and crossed over to desipramine,) One patient refused evaluation on DSM-III-R throughout; 2 patients, both on desipramine, dropped out because of adverse effects (seizure, mania). In addition, there was statistically significant (p = .001) improvement over time and different rates of improvement over time in the treated and untreated groups for the affect/mood scale data., Conclusion: Results from this small study, utilizing a blinded, placebo lead-in design appear to (1) demonstrate the clinically significant effectiveness of desipramine in treating long-standing depression in a series of patients with severe traumatic brain injury, as rated with DSM-III-R criteria; (2) show statistically significant improvement on the affect/mood scale data, favoring the treated versus untreated (placebo lead-in) group.

HU-211 (Dexanabinol), a putative neuroprotective agent, was evaluated in a number of animal models including closed head injury, optic nerve crush, global ischemia and focal ischemia. In these models, a single injection of HU-211 given after the insult confers long term functional improvement and significant increase in neuronal survival. Neuroprotective doses of HU-211 were found to be safe in a 14 day toxicological study in two species. In terms of mechanism, the compound behaves as a noncompetitive NMDA antagonist in vitro and in vivo. It blocks NMDA stimulated calcium influx in primary neuronal culture, and head injury related calcium influx in rats. In addition, HU-211 is a potent scavenger of peroxy and hydroxy radicals in vitro and it protects cultured neurons from toxicity of radical generators. Thus, Dexanabinol holds a unique position among putative neuroprotective agents since it combines NMDA blocking activity and free radical scavenging properties in one molecule. These observations support the development of HU-211 as a novel, multiple-action treatment approach for brain damage associated with stroke, cardiac arrest and trauma.

Delusional misidentification syndromes (DMS) are beginning to be well described clinically but little is known about their epidemiology. To try and obtain an estimate of their prevalence, a survey was performed of all admissions to a locked psychiatric inpatient unit from April 1983 to June 1984. 26 patients satisfied clinical criteria for DMS during this time and overall 835 patients were admitted to the unit. Thus, a crude prevalence of 3.1% was found. The median age of the patients was 29 years. The overwhelming majority had a principal psychiatric diagnosis of paranoid schizophrenia and only 2 of an affective disorder. By a small margin, most patients were male. The implications and limitations of these findings are discussed.

Pharmacological interventions in the treatment of various cognitive, behavioural and neurological problems after brain injury often may involve combinations of medications from various drug classes. This carries the implication of potentially new or previously underreported drug interactions. A case report is presented in which a commonly used anticonvulsant drug, valproic acid, and a commonly used antidepressant, desipramine, interacted in such a manner as to cause potentially toxic serum concentrations of desipramine. This case demonstrates the important point that it is not simply the addition of one drug to another that may cause interaction, but the withdrawal of a particular drug which may then adversely impact the remaining drug regimen.

The results of a series of eight individual case reports in which protriptyline, an activating tricyclic antidepressant, was used as a 'stimulant' medication are presented. For some patients with head injury, traditional stimulants, such as methylphenidate, or dopaminergic stimulants, such as levodopa-carbidopa, amantadine, or bromocriptine, may be partially or totally ineffective or not tolerated. Protriptyline can be a very effective alternative and, for some patients, may be the most effective stimulant tried. In low to moderate doses, protriptyline should be considered for trials as an activating/stimulant medication in patients with head injury.

An experiment was carried out designed primarily to test A B Joseph's suggestion that patients with Capgras delusion may have problems integrating information between the two cortical hemispheres; and at the same time it was meant to examine J Cutting's ideas linking schizophrenia in general, and the Capgras delusion in particular, to right hemisphere dysfunction. Three patients with the Capgras delusion and three matched controls diagnosed as paranoid schizophrenics were briefly presented pairs of line-drawn object and photographs of faces randomly in the left visual field, the right visual field or bilaterally. The results with objects revealed no particular pattern of performance for either group; but, when faces were shown, the controls revealed the usual left visual field/right hemisphere advantage while for the Capgras group this was reversed. The results are not consistent with a simple prediction from Joseph's hypothesis but they are in accord with Cutting's theory-though they also pose some problems for it, which are discussed.

Akathisia is frequently reported to be caused by neuroleptic drugs and sometimes by certain other agents such as fluoxetine. Benzodiazepines are a common treatment. The principal mechanism of akathisia is thought to be neurochemical, probably dopaminergic with serotonin also playing an important role. It is not usually thought to be related to benzodiazepine-caused disinhibition. Four episodes of atypical or paradoxical benzodiazepine-induced akathisia in three patients are reported and analyzed. All four episodes of akathisia were atypical because they were caused by clonazepam, clorazepate, or lorazepam. In one patient neither thiothixene nor lorazepam caused akathisia, but clonazepam and clorazepate did. In another patient both lorazepam and fluoxetine caused akathisia. It is also noted that all three patients had a history of traumatic brain injury and seizure disorder. The data support the hypothesis that atypical benzodiazepine-induced akathisia exists. Its mechanism may be different from neuroleptic-induced akathisia, but may still involve serotonergic systems or the forced normalization phenomenon. The similarity of these cases to reports of benzodiazepine-induced disinhibition raises the possibility that in some patients they may be the same entity.

Brain-injured patients involved in rehabilitation programs are susceptible to the occurrence of acute seizures or severe behavioral episodes. Effective pharmacological management in this setting should ideally include rapid onset without severe adverse effects. Previous treatments have generally included intramuscular diazepam or lorazepam, as well as intramuscular antipsychotic drugs. These options have proved problematic due to poor absorption, slow onset of activity, or potential for unacceptable side effects. We report 10 cases involving the use of intramuscular midazolam, a rapid-acting, short half-life benzodiazepine, in treating acute seizures or behavioral problems. We conclude that this drug demonstrates great promise for the rapid, effective treatment of these conditions without significant adverse effects and deserves further study in these areas.

Two cases of transient stuttering occurring in association with catatonia and bipolar disorder are described. Affective decompensation has been associated with lateralized cerebral dysfunction, and it is hypothesized that in some bipolar catatonic patients a concomitant disorder of the lateralization of language function may lead to a variety of clinical presentations including aphasia, mutism, and stuttering.

The computed tomographic scans of 12 patients with Capgras syndrome and 12 matched controls were blindly assessed. A variety of statistical comparisons between the two groups consistently showed that patients with Capgras syndrome had significantly more bilateral frontal and temporal lobe atrophy. Capgras syndrome may be associated with dysfunction of these areas. Interestingly, all of the index patients had paranoid schizophrenia, and these results suggest the hypothesis that in some schizophrenic patients the presence of Capgras syndrome may be a marker for the coexistence of a focal idiopathic neurodegenerative process that preferentially affects the anterior cerebrum bilaterally.

Forty-eight consecutive psychiatric outpatients receiving neuroleptics were assessed for handedness and the presence of tardive dyskinesia (TD). Twenty-seven patients had TD and 21 did not. Twenty-one of the patients with TD had some degree of non-right-handedness compared with 3 of the patients without TD. These results were found to be statistically significant. Maleness also correlated with the presence of TD, but the results were less robustly significant. These findings indicate that non-right-handedness and maleness may correlate with the risk of developing TD. To the author's knowledge, these findings have not been previously reported.

Permanent injury to the nervous system can occur in a number of ways and lead to profound residual disability. Attempts to restore function are being made by many different groups. They range from prosthetic repair to pharmacological intervention. A theoretical framework within which injuries can be analysed and understood is desirable. One is proposed. From it a rational set of approaches to the restoration of nervous system function is generated. These are outlined.

Two patients are described who wrote complex textual material suddenly, automatically, and without volitional control. Each met DSM-III criteria for a major affective disorder, had clinical and electrophysiologic temporal lobe epilepsy, absence spells, episodic expressive aphasia, and a history of traumatic loss of consciousness. The episodes of automatic writing met the criteria for ictal events. These patients may have experienced an ictal analogue of interictal hypergraphia. The behavioral neurologic features of this syndrome are discussed in relation to its clinical presentation and known disorders of writing.

Bulimia, a disorder of episodic binging and purging, remains without a known etiology. A case report is presented of a patient who attributed bulimic episodes to efforts at inducing euphoria. Experimental pain tolerance was increased by bulimic vomiting, blocked by naloxone, but not by saline. Vomiting was also associated with falls in depression and anxiety. Plasma ACTH and cortisol, putative markers for beta-endorphin, also rose following vomiting. It is hypothesized that in some bulimics, the disorder arises by virtue of an addiction to one's own internally released endogenous opioid peptides.

The hallmark of Cotard's syndrome is the delusion of being dead. The literature indicates that it is often associated with parietal lobe lesions. This association was investigated by blindly comparing the computed tomographic scans of eight patients who had Cotard's syndrome (one of whom is described) with those of eight controls matched as closely as possible for age, sex, race, and principal psychiatric diagnosis. Two trends emerged. Compared with controls, patients with Cotard's syndrome had more brain atrophy in general and more median frontal lobe atrophy in particular. Parietal disease did not discriminate between the index and control groups. Cotard's syndrome may be associated with multifocal brain atrophy and medial frontal lobe disease.

A patient with chronic psychosis and intermittent psychotic misidentification of the Capgras and intermetamorphosis types refractory to neuroleptic treatment was given a trial of clorazepate. Complete remission of psychotic symptoms was achieved for the first time in 19 years, but these recurred when the patient discontinued her clorazepate. It is concluded that clorazepate may be a useful treatment for some cases of chronic psychosis and psychotic misidentification. A possible mechanism for this is discussed.

The hallmark of Cotard's syndrome is the delusion of being dead. It is usually seen in affective disorders, and its existence as a separate entity is controversial. A patient is described who presented with paranoid schizophrenia, Cotard's syndrome, the misidentification syndromes of Capgras and subjective doubles, and palinopsia (visual perseveration). Focal theories for these conditions are briefly outlined and the patient is discussed with reference to them. It is proposed that this case supports the concept that Cotard's syndrome is a distinct disorder. The possibility of cerebral dysfunction in the confluence of the parietal, temporal, and occipital regions accounting for this specific clinical presentation is considered.

In a model for multiple laparoscopies proliferation of T-lymphocytes was an early, but transitory, immunologic reaction in the spleen to intraperitoneal CO2 insufflation. Intraperitoneal insufflations of approximately 3.5 ml of CO2 were given daily to three groups of BALB/c mice for 11, 20, and 32 consecutive days, respectively. Air insufflation was given to experimental controls. The observations in the insufflation model are summarized as follows: 1) Multiple CO2 insufflation approximately doubled the number of splenic T lymphocytes. 2) The percentage value was highest on the day of the last insufflation. The difference between this value in each of the three groups was statistically not significant; ie, there was no dose-response relationship in the range of 11-32 insufflations. 3) There was a dose-response effect in the range of 3-9 insufflations. 4) The number of splenic T lymphocytes decreased with each day after the end of treatment. Untreated control values were reached in 12-16 days. 5) Air insufflation had only a minimal effect on the proliferation of T lymphocytes in the spleen. In this model there is correlation between early proliferation of T lymphocytes in the spleen and the late occurrence of a high incidence of malignant lymphoma (approximately 60%). The long-term survivors of CO2 insufflation also developed a wide spectrum of intraabdominal malignancies. It was speculated that CO2 insufflation provided an abnormal internal environment that affected a variety of target tissues. Prolonged CO2 accumulation might have modified nucleic acid structure via chronic intracellular acidosis. Could the neoplastic sequelae in this model be a clue to a similar sequel in humans after multiple laparoscopies?

Implantation of prosthetic devices designed to complement the function of the human brain is a rare but well recognized innovative treatment for some patients. If this technique is to become clinically useful special attention will have to be paid to the bio-engineering requirements of the prosthesis-brain interface.

Based on the cholinergic-deficiency hypothesis of tardive dyskinesia (TD), we administered cytidine diphosphoryl choline (CDP-Choline) (a naturally occurring biochemical intermediary in the synthesis of phosphatidylcholine), 500 mg twice a day orally, to four women and one man with TD for 2 to 8 weeks in a double-blind, placebo-controlled crossover trial. Although the small sample size provides only limited power to detect a treatment effect, there was no evidence of efficacy, adverse effects, or changes in psychopathology.

The computed tomography scans of 10 patients with Fregoli syndrome and 10 matched controls were blindly assessed. Patients with Fregoli syndrome showed more frontal and temporal lobe atrophy than controls. Fregoli syndrome may be associated with dysfunction of these areas.

Metabolic carcinogenesis may be viewed as a process in which a chronic disturbance of metabolic homeostasis leads to malignancy. Fluctuation in the CO2 tension in tissues is accompanied by changes in the intracellular pH. This prompted investigations into the long-term clinical effects of high CO2 tensions on various normal tissues in mice by two different methods. The first consisted of exposing different tissues in vitro to a high CO2% in air before transplantation into syngeneic or autologous hosts. The second method consisted of exposing intraperitoneal tissues in vivo to CO2-infusion, thus avoiding graft-host interactions. This is a report of the most significant findings in the series of investigations analyzed, 1. High incidences of malignant lymphoma in strains of mice with a low or zero spontaneous incidence followed: (a) syngeneic transplantation, (b) autologous transplantation, (c) in vivo exposure to CO2-infusion. 2. Syngeneic graft recipients developed similar high lymphoma incidences, irrespective of the tissue grafted or the pretransplantation treatment of the graft. 3. In the autologous system, however, the clinical results reflect the differences in the pretransplantation treatment, in contrast to those in the syngeneic system. 4. Whereas intraperitoneal CO2-infusion induced lymphoma, air-infusion did not. 5. Non-lymphoid grafts exposed in vitro to elevated CO2 induced only lymphoid malignancies. But non-lymphoid tissues exposed in vivo to elevated CO2 developed tumors of other tissues, such as lung tumor, in addition to lymphoid malignancies. 6. The same morphological lymphoid abnormalities occurred in all lymphoma-developing animals in these three experimental models. Hyperplasia in the splenic T-cell areas appeared most frequently. 7. The presence of immune-associated lesions in experimental animals (amyloidosis, interstitial nephritis and myocarditis) points to the activation of immune mechanisms in this lymphoma development. The evidence as a whole suggests the possibility that chronic immunological stimulation of host lymphoid tissue may be involved in the development of lymphoid malignancies in these animal models.

In koro, the sensation of penile retraction is coupled with an intense fear that death will occur once the retraction is complete. Koro has been reported mainly in Southeast Asia, and it occurs in both epidemic and sporadic forms. Two cases, the first each in natives of Haiti and Ethiopia, are presented. Similarities between them and computed tomography and brain electrical activity mapping data are used to support the concept that sporadic koro may be a form of right temporoparietal or bitemporoparietal dysfunction similar to sexual epilepsy. The hypothesis is advanced that epidemic koro occurs in permissive cultures when groups of individuals imitate sporadic koro.

Previously, malignant lymphomas in mice have been found to be the late sequelae of the autologous transplantation of skin grafts pretreated with CO(2); these did not occur with grafts cultured in air alone. The clinical result in this autologous system reflects environmental differences in vitro (Goldsmith & Narvaez 1975). In the present study the syngeneic transplantation in BALB/c mice of lymph node tissue resulted in the late appearance of malignant lymphomas (48-69%), irrespective of the pretransplantation treatment of the grafts. Lymph node grafts were exposed to three different environments before transplantation into syngeneic hosts: (1) to culture in air (24 hours); (2) to culture in an atmosphere of 45% CO(2) in air (24 hours); (3) direct transplantation without in vitro exposure. Transplantation of these three groups of differently treated grafts was followed by the same clinical results in their recipients. These were: (1) The development of lymphoma whereas the spontaneous incidence was zero. (2) The proliferation of T-lymphocytes in the spleen; the incidence of this abnormality correlates with the lymphoma incidence. (3) A higher than normal occurence of immune-associated lesions (amyloidosis, interstitial nephritis and myocarditis). Both syngeneic and autologous transplantations may serve as animal models for the study of clinical malignant lymphoma.

The computerized tomographic scans of five catatonic patients and five matched controls were blindly assessed. The catatonic patients showed preponderant atrophy of the brainstem and cerebellar vermis. Catatonia may be associated with lesions in these areas.